Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Epub 2020 Sep 11. This trial was registered at www.clinicaltrials.gov as #NCT02946463. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence … Correspondence: Jong Wook Lee, Department of Hematology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; e-mail: jwlee@catholic.ac.kr. In the pivotal phase‐3 trial of ravulizumab vs. eculizumab in treatment‐naïve PNH patients, the weighted average of proportions of LDH normalization (LDH < 246 U/L) from day 29 to 183 was the co‐primary endpoint of the study. A complete list of ALXN1210-PNH-301 study investigators appears in the supplemental appendix. Hemoglobin levels were evaluated before randomization and within 5 days before study drug initiation; patients were transfused, if necessary, to reach the protocol-specified hemoglobin level. For the LDH normalization (LDH-N) end point, adjusted prevalence within each treatment is displayed. 2020 Oct;112(4):466-476. doi: 10.1007/s12185-020-02934-6. Patients within each of the 6 groups were randomly assigned in a 1:1 ratio to receive ravulizumab or eculizumab (supplemental Appendix Section 3; supplemental Figure 1). Data regarding packed red blood cell transfusions, incidence of MAVEs, and clinical manifestations of PNH are summarized in Table 3. All patients gave written informed consent. The adjusted prevalence of LDH normalization was 53.6% for the ravulizumab group and 49.4% for the eculizumab group; the adjusted OR for comparison of ravulizumab vs eculizumab was 1.19 (95% CI, 0.80, 1.77; Pinf < .0001). Ravulizumab: a complementary option for PNH. Complement as a Therapeutic Target in Systemic Autoimmune Diseases. AEs are summarized in Table 4. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? Transfusion requirements and elevated hemolysis (LDH levels ≥1.5× ULN) are both important measures of PNH disease severity1,3,12  and are associated with negative outcomes in patients with PNH.12,23  Transfusion is both a supportive modality and an important measure of disease activity before and during treatment. Rituximab and eculizumab when treating nonmalignant hematologic disorders: infection risk, immunization recommendations, and antimicrobial prophylaxis needs. Key secondary end points included percentage change from baseline to day 183 in LDH and change from baseline to day 183 in quality of life, as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue scale, version 420,21 ; the proportion of patients with breakthrough hemolysis, defined as ≥1 new or worsening sign or symptom of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], MAVEs including thrombosis, dysphagia, or erectile dysfunction) in the presence of LDH ≥2× ULN after prior reduction of LDH to <1.5× ULN on treatment, and proportion of patients with stabilized hemoglobin, defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion. Mean LDH levels decreased and normalized rapidly after initiation of study drug, and LDH normalization was sustained through the 26-week treatment period. See this image and copyright information in PMC. The intravenous ravulizumab group received a loading dose (2400 mg for patients weighing ≥40 to <60 kg, 2700 mg for patients ≥60 kg to <100 kg, and 3000 mg for patients ≥100 kg) on day 1, followed by maintenance doses of ravulizumab (3000 mg for patients ≥40 to <60 kg, 3300 mg for patients ≥60 to <100 kg, and 3600 mg for patients ≥100 kg) on day 15 and every 8 weeks thereafter. Patients assigned to eculizumab received induction doses of 600 mg on days 1, 8, 15, and 22, followed by maintenance dosing of 900 mg on day 29 and every 2 weeks thereafter per the approved PNH dosing regimen.4,5. The model included LDH normalization as the dependent variable and an indicator variable for treatment, history of transfusion (as a categorical variable based on the stratification factor levels), and baseline LDH level (as a continuous variable). The most frequently reported AE was headache (36.0% and 33.1% in the ravulizumab and eculizumab groups, respectively). Ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria. COVID-19 is an emerging, rapidly evolving situation. Red blood cell transfusions were administered when patients had a hemoglobin level ≤9 g/dL with anemia-related signs or symptoms of sufficient severity to warrant transfusion or a hemoglobin level ≤7 g/dL regardless of the presence of clinical signs or symptoms. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (P inf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), … Eculizumab Remove Eculizumab from your drug comparison Soliris … Unable to load your collection due to an error, Unable to load your delegates due to an error. The stratified Newcombe method was used to calculate 95% CIs for TA. developed the protocol, recruited patients, and collected data, analyzed and interpreted the data, contributed to the manuscript, and approved the final version; F.S.d.F., L.W.L.L., V. Pessoa, S.G., W.F., and V. Ptushkin contributed to the manuscript and approved the final version; S.T.R., L.V., L.S., R.A., and R.P. V. Ptushkin has received honoraria from Alexion Pharmaceuticals, Inc. Ravulizumab treatment was concluded to be noninferior to eculizumab if the lower bound of the 95% CI for the difference (ravulizumab − eculizumab) was greater than the noninferiority margin of −15%. Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. Statistical analysis, pharmacokinetic/pharmacodynamic assessments, and editorial review were provided by Andrew I. Damokosh and Stephan Ortiz of Alexion Pharmaceuticals, Inc. Editorial review was also provided by Kenneth Pomerantz of Alexion Pharmaceuticals, Inc. Baseline LDH was defined as the average of all available assessments before the first infusion of study drug. Portions of this work were presented at the 23rd Congress of the European Hematology Association, Stockholm, Sweden, 14-17 June 2018. *Red triangle indicates the noninferiority margin. FOIA Epub 2018 Dec 3. Ravulizumab provided immediate, complete, and sustained inhibition … Ravulizumab is a newly approved treatment for paroxysmal nocturnal hemoglobinuria that may reduce breakthrough hemolysis risk, thus improving health-related quality of life and … Ravulizumab and eculizumab were well tolerated in this study. Demographics and baseline clinical characteristics. Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). If you have been using another drug called eculizumab , you will need to wait 2 weeks after your last dose of eculizumab before starting treatment with Ultomiris. Ishiyama K, Nakao S, Usuki K, Yonemura Y, Ikezoe T, Uchiyama M, Mori Y, Fukuda T, Okada M, Fujiwara SI, Noji H, Rottinghaus S, Aguzzi R, Yokosawa J, Nishimura JI, Kanakura Y, Okamoto S. Int J Hematol. The robust results observed in this study across a broad selection of clinically relevant end points, despite the challenges of using a highly efficacious comparator, reflect treatment of a large patient population, high compliance with respect to study execution, and statistical rigor. ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and scientific validity … Ravulizumab was noninferior to eculizumab on the 4 key secondary end points (Figure 1B; Table 2), with all point estimates consistently favoring ravulizumab. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. The online version of this article contains a data supplement. There were no noteworthy differences between treatment groups in demographics or baseline clinical characteristics (Table 1). For all efficacy end points, the large differences between the boundaries of the CIs and noninferiority margins establish the strength of evidence of the study results. has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. F.S.d.F. National Library of Medicine Ravulizumab met the prespecified noninferiority threshold with 73.6% of study participants avoiding transfusion whereas 66.1% of those receiving eculizumab avoided transfusion. Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Blood. has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. F.S.d.F. Cells. BL, baseline (the last nonmissing assessment value before first dose of study drug). All analyses were performed using SAS (SAS Institute Inc, Cary, NC), version 9.4, or higher or other validated statistical software. Half-life of eculizumab is 11.25-17.25 days. The less-frequent, every-eight-week dosing with ravulizumab appeared to be associated with better quality of life, compared with eculizumab: A higher proportion of ravulizumab-treated … are employees and stockholders of Alexion Pharmaceuticals, Inc. H.S. Additional secondary end points included time to first occurrence of LDH normalization, total number of packed red blood cell units transfused, change in clinical manifestations of PNH, change from baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 Scale (EORTC QLQ-C30), version 3.0,22  proportion of patients experiencing MAVEs (including thrombosis), and change in free C5 concentrations. eCollection 2019. The coprimary end points were: (1) transfusion avoidance (TA), defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183; and (2) hemolysis as measured by LDH normalization (ULN, 246 U/L) from days 29 through 183. Noninferiority of ravulizumab was based on the coprimary end points and defined as: (1) the lower bound of the 95% confidence interval (CI) for the difference in TA rate between ravulizumab and eculizumab being greater than −20%, and (2) lower bound of the 95% CI for the odds ratio (OR) of ravulizumab vs eculizumab for LDH normalization being greater than an OR of 0.39. In addition, 11% to 27% of patients may experience breakthrough hemolysis,9-11  placing patients at risk for thrombotic events and other potentially life-threatening complications associated with intravascular hemolysis.12,13. Eighty-five of 97 patients (87.6%) receiving ravulizumab and 81 of 98 patients (82.7%) receiving eculizumab … Of the 15 breakthrough hemolysis events in the eculizumab group, 7 were associated with inadequate terminal complement inhibition, 4 were associated with infections, and 4 had no determined cause. Immunogenicity was low with 1 treatment-emergent antidrug antibody–positive sample in each treatment arm. Free C5 levels <0.5 µg/mL are associated with complete inhibition of C5 activity. Safety analyses were performed on the safety set, defined as all patients who received ≥ 1 dose of study drug. The study consisted of a 4-week screening period and a 26-week randomized treatment period to evaluate the efficacy and safety of ravulizumab vs eculizumab, followed by an extension period of up to 2 years, during which all patients receive ravulizumab (supplemental Appendix Section 3; supplemental Figure 1, available on the Blood Web site). Enrollment of patients without a history of transfusion in the past year was capped at 20%. The mean (SD) total number of packed red blood cell units transfused during the treatment period was comparable in the ravulizumab (4.8 [5.1]) and eculizumab (5.6 [5.9]) groups. Twenty patients experienced serious AEs (11 ravulizumab and 9 eculizumab patients); pyrexia was the only serious AE reported in >1 patient (1 ravulizumab patient and 2 eculizumab patients). Ravulizumab was found to be non-inferior to eculizumab for both coprimary endpoints . Ravulizumab (Alexion Pharmaceuticals, Inc.), a humanized monoclonal antibody that blocks terminal complement activation at C5, was engineered from eculizumab, resulting in a molecule that targets … are employees and stockholders of Alexion Pharmaceuticals, Inc. H.S. This event of mesenteric venous thrombosis with concurrent neutropenic colitis occurred in a patient who had history of aplastic anemia. The authors thank the investigators of ALXN1210-PNH-301, who are listed in supplemental Appendix Section 1. Search for other works by this author on: The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria, Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria, Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria, Soliris (eculizumab); prescribing information, Soliris (eculizumab); summary of product characteristics, Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria [published correction appears in Nat Biotechnol. Serious infections observed in patients treated with ravulizumab included leptospirosis and systemic infection (causative agents not identified); serious infections observed in patients treated with eculizumab included limb abscess, cellulitis, infection, pneumonia, and viral upper respiratory tract infection (causative agents not identified). In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. has received honoraria from Alexion Pharmaceuticals, Inc, and Novartis. For the LDH-N end point, the adjusted prevalence within each treatment is displayed. Ultomiris ravulizumab Remove Ultomiris from your drug comparison. The new results come from an open-label, multicenter trial, presented here at the European Hematology Association (EHA) 2018 Congress. Pharmacodynamic analyses were performed on all patients who received ≥1 dose of study drug and had evaluable pharmacodynamic data. Indeed, presence of ≥1 reported PNH-related symptom in addition to hemolysis confers particularly high risk of thrombosis-related complications.12,25  Complement inhibition mitigates these poor outcomes26  through the inhibition of intravascular hemolysis, stabilization of hemoglobin levels, and reduced need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02946463. From a patient and health care perspective, a fourfold longer dosing interval of ravulizumab vs eculizumab may reduce treatment burden and health care resource utilization and may expand access to patients who are unable to comply with the every-2-week dosing of eculizumab. The between-group difference in least-squares mean percentage change in LDH levels was −0.83% (95% CI, −5.21, 3.56; Pinf < .0001); least-squares mean difference in change in FACIT-Fatigue score was 0.67 (95% CI, −1.21, 2.55; Pinf < .0001). The protocol was approved by the institutional review board or independent ethics committee at each participating center, and the study was conducted in accordance with the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. For the transfusion avoidance end point, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. The authors thank Rodrigo Pavani and Masayo Ogawa of Alexion Pharmaceuticals, Inc, for their contribution to the implementation of the study. Ravulizumab provided immediate, complete, and sustained inhibition of C5 over the entire 8-week dose interval, unlike eculizumab. The lower bound of the 95% CI was greater than the protocol-specified noninferiority margin of 0.39. 2007;25:1488], Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study, Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival, Eculizumab dosing intervals longer than 17 days may be associated with greater risk of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria, Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria, Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab, Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry, Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry, Immediate, complete, and sustained inhibition of C5 with ALXN1210 reduces complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH): interim analysis of a dose-escalation study [abstract], First in human single-ascending dose study: safety, biomarker, pharmacokinetics and exposure-response relationships of ALXN1210, a humanized monoclonal antibody to C5, with marked half-life extension and potential for significantly longer dosing intervals [abstract], Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action, Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies, Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study, Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system, Fatigue in cancer patients compared with fatigue in the general United States population, The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology, Predictive factors of mortality in population of patients with paroxysmal nocturnal hemoglobinuria (PNH): results from a Korean PNH registry, Clinical course and disease burden in patients with paroxysmal nocturnal hemoglobinuria by hemolytic status, The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease, Effect of eculizumab in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high disease activity: results from the International PNH Registry [abstract], Genetic variants in C5 and poor response to eculizumab, Infectious diseases associated with complement deficiencies, Interim analysis of safety outcomes during treatment with eculizumab: results from the International Paroxysmal Nocturnal Hemoglobinuria Registry [abstract 3486], High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine, © 2019 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, https://doi.org/10.1182/blood-2018-09-876136, Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study, Ravulizumab: a complementary option for PNH, Age at first infusion of study drug, mean (SD), y, Number of years from PNH diagnosis to consent, median (minimum, maximum), y, History of major adverse vascular events, n (%), LDH, least squares mean % change (95% CI), FACIT-Fatigue score, least squares mean change (95% CI), Hemoglobin stabilization rate, % (95% CI), Patients who received packed RBC transfusions, n (%), Total number of packed RBC units transfused, mean (SD), Patients with major adverse vascular events, n (%), Patients with AEs leading to withdrawal of study drug, n (%), Patients with serious AEs leading to withdrawal of study drug, n (%).
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