ravulizumab vs eculizumab

2019 Feb 7;133(6):503-504. doi: 10.1182/blood-2018-12-891499. Median (95% CI) time to first occurrence of LDH normalization was 5 days shorter in the ravulizumab group (24 [22, 29] days vs 29 [24, 43] days). Antibody titers were low (≤1) and not neutralizing, with no apparent effects on pharmacokinetics/pharmacodynamics or safety. National Library of Medicine Routine prophylactic antibiotic treatment was otherwise optional. Ultomiris ravulizumab Remove Ultomiris from your drug comparison. 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). The safety profile of ravulizumab in patients with PNH who were naive to complement inhibitor therapy was comparable to that of eculizumab.1,2,10  As observed in previous studies with eculizumab,1,2,10  the most frequently reported AE was headache. has received honoraria and research support (all to University of Ulm) from Alexion Pharmaceuticals, Inc. A.H. has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. L.W.L.L. Further details regarding data availability, instructions for requesting information, and our data disclosure policy will be available on the Alexion Web site (http://alexion.com/research-development). Nonetheless, because terminal complement plays a major role in prevention of meningococcal disease6,28  and patients treated with eculizumab are at increased risk for meningococcal infection, it is expected that this would also be the case for ravulizumab.4,5,29,30. has received honoraria and research support (to St. Louis Hospital) from Alexion Pharmaceuticals, Inc. V. Pessoa and S.G. have received research support from Alexion Pharmaceuticals, Inc. W.F. The key secondary end points were tested in a hierarchical manner if noninferiority was declared for the coprimary end points. There were no discontinuations of ravulizumab and 2 discontinuations of eculizumab during the randomized treatment period, 1 due to a physician’s decision and 1 patient withdrew consent. Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients. 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 every 8 weeks is noninferior to eculizumab every 2 weeks across all efficacy end points in C5 inhibitor–naive PNH patients. 2021 Jan 13;10(1):148. doi: 10.3390/cells10010148. has received honoraria from Alexion Pharmaceuticals, Inc, and Novartis. Ravulizumab was found to be non-inferior to eculizumab for both coprimary endpoints . 2020 Nov;95(11):1334-1343. doi: 10.1002/ajh.25960. Ravulizumab and eculizumab were well tolerated in this study. Schrezenmeier H, Kulasekararaj A, Mitchell L, Sicre de Fontbrune F, Devos T, Okamoto S, Wells R, Rottinghaus ST, Liu P, Ortiz S, Lee JW, Socié G. Ther Adv Hematol. S.T.R., L.V., L.S., R.A., and R.P. Across sensitivity … (B) For key secondary end points LDH-PCHG (percent change), breakthrough hemolysis (BTH), and hemoglobin stabilization (HGB-S), Diff (95% CI) is based on estimated differences in percent with 95% CI. All patients gave written informed consent. Comparing Eculizumab vs Soliris. History of major adverse vascular events (MAVEs) was not a component of the randomization stratification criteria. The other patient had history of lower leg pain and edema and was taking an oral anticoagulant, which was discontinued after initiation of study drug. Coprimary and key secondary efficacy outcomes at day 183. Background: Paroxysmal nocturnal hemoglobinuria, characterized by intravascular hemolysis and venous thrombosis, can be managed with eculizumab, an inhibitor of the complement system; however, patients may periodically experience breakthrough hemolysis. Other serious infections occurred in 2 patients (1.6%) in the ravulizumab group and 4 (3.3%) in the eculizumab group. 2020 Mar;20(3):227-237. doi: 10.1080/14712598.2020.1725468. This outcome is clinically relevant for patients with PNH, some of whom do not achieve complete disease control with the current standard of care, labeled-dose eculizumab (900 mg every 2 weeks as maintenance).9-11  Therefore, the results of this study demonstrating a trend favoring ravulizumab for all 6 end points are most likely driven by the sustained inhibition of C5 associated with ravulizumab. Efficacy analyses were performed on the full analysis set, which included all patients who received ≥ 1 dose of ravulizumab or eculizumab and had ≥ 1 efficacy assessment after the first infusion. Ravulizumab achieved complete terminal complement inhibition (defined as serum free C5 <0.5 μg/mL) by the end of the first infusion, which was sustained throughout the 183-day treatment period in all patients. Accessibility PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cell; SD, standard deviation. Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. F.S.d.F. Patients were stratified into 6 groups based on transfusion history (0, 1-14, or >14 units of packed red blood cells in the 1 year before the first dose of study drug) and LDH screening level (1.5 to <3 times the upper limit of normal [ULN] or ≥3× ULN). eCollection 2019. Ravulizumab is a newly approved treatment for paroxysmal nocturnal hemoglobinuria that may reduce breakthrough hemolysis risk, thus improving health-related quality of life and … Epub 2020 Aug 31. 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. Ravulizumab provided immediate, complete, and sustained inhibition … Free C5 levels <0.5 µg/mL are associated with complete inhibition of C5 activity. A complete list of ALXN1210-PNH-301 study investigators appears in the supplemental appendix. Baseline LDH was defined as the average of all available assessments before the first infusion of study drug. Pre-discontinuation treatment contributed the largest proportion of total costs for ravulizumab (94.8% and 88.0%) and eculizumab (94.8% and 87.8%) in adults and children, respectively. Patients who initiated study drug treatment <2 weeks after receiving a meningococcal vaccine were required to receive treatment with appropriate prophylactic antibiotics until at least 2 weeks after vaccination. 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. Data from days 1, 15, 71, and 127 are from predose and end of infusion for both treatment groups, whereas at days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155, and 169, the data are from any time for the ravulizumab group and predose for the eculizumab group; and at day 183, data are from end of the randomized treatment period for both treatment groups. The authors thank Rodrigo Pavani and Masayo Ogawa of Alexion Pharmaceuticals, Inc, for their contribution to the implementation of the study. Expert opinion: In phase 3 trials, ravulizumab has been shown to be as safe and efficacious as eculizumab, to be associated numerically with lower rates of breakthrough hemolysis (p for non-inferiority <0.0004), and to be preferred over eculizumab by most patients. Full eligibility criteria are presented in supplemental Appendix Section 2). For the LDH normalization (LDH-N) end point, adjusted prevalence within each treatment is displayed. Patients with PNH who had not previously been treated with complement inhibitors were randomly assigned to treatment with ravulizumab (n = 125) or eculizumab (n = 121) for 26 weeks.Mean patient age was 44.8 years in the ravulizumab group and 46.2 years in the eculizumab group, and the m… The sponsor and investigators also thank the patients and their families for their participation in and support for this clinical study. The authors thank the investigators of ALXN1210-PNH-301, who are listed in supplemental Appendix Section 1. In the ravulizumab arm, 73.6% of participants avoided transfusion and 53.6% of participants had … Portions of this work were presented at the 23rd Congress of the European Hematology Association, Stockholm, Sweden, 14-17 June 2018. Serious AEs in the ravulizumab group included: anemia, aplastic anemia, neutropenia, thrombocytopenia, left ventricular failure, myocardial ischemia, pyrexia, leptospirosis, systemic infection, laceration, uterine leiomyoma, renal colic, and deep vein thrombosis (n = 1 patient each). 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. *Red triangle indicates the noninferiority margin. Immunogenicity was low with 1 treatment-emergent antidrug antibody–positive sample in each treatment arm. The online version of this article contains a data supplement. a The mean (SD) terminal elimination half-life and clearance of ravulizumab-cwvz in patients with PNH are 49.7 (8.9) days and 0.08 (0.022) L/day, respectively. This trial was registered at www.clinicaltrials.gov as #NCT02946463. The percentage of patients with a ≥3-point improvement in FACIT-Fatigue score was similar between the ravulizumab and eculizumab groups (37.1% vs 33.7%). ‡P < .06 for the lower bound of the 95% CI. Ravulizumab provided immediate, complete, and sustained inhibition of C5 over the entire 8-week dose interval, unlike eculizumab. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for both coprimary end points and all 4 key secondary efficacy end points by providing immediate, complete, and sustained inhibition of terminal complement with a safety profile similar to that of eculizumab. This trial was registered at www.clinicaltrials.gov as #NCT02946463. 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. Add to compare. The humanized monoclonal antibody eculizumab (Soliris ®) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody-positive adults with generalized myasthenia gravis (gMG) … For the transfusion avoidance end point, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. Would you like email updates of new search results? This threshold was not consistently met in patients receiving eculizumab (Figure 3). 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). The sample size estimate based on LDH normalization was smaller than that based on TA (minimum of 142 patients required to provide 80% power). Within 3 months of screening, ≥1 of the following PNH-related signs or symptoms must have been present: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (ie, hemoglobin level <10 g/dL), or history of MAVEs (including thrombosis), dysphagia, erectile dysfunction, or history of packed red blood cell transfusion because of PNH. 2020 Oct;112(4):466-476. doi: 10.1007/s12185-020-02934-6. See this image and copyright information in PMC. Please enable it to take advantage of the complete set of features! 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. The coprimary end point TA was evaluated as the proportion of patients achieving the end point, computed as a weighted combination of differences between the treatment groups within the 2 randomization stratifications, using Mantel-Haenszel tests. For the TA end point, treatment differences (Diff) (95% CI) are based on estimated differences in percent with 95% CI. 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. After each infusion, you will be watched closely for at least 1 hour to make sure you do not have an allergic reaction. A safety review committee performed safety monitoring, and an independent data monitoring committee was in place to monitor meningococcal infections. 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. The lower bound of the 95% CI was greater than the protocol-specified noninferiority margin of 0.39. Complement as a Therapeutic Target in Systemic Autoimmune Diseases. declares no competing financial interests. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. 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. Free C5 levels were assessed using a Gyros-based fluorescence assay in patients who received ravulizumab and an electrochemiluminescent immunoassay in patients who received eculizumab; 3 patients in the ravulizumab group and 8 in the eculizumab group had day 1 samples excluded because the samples were considered biologically implausible. The lower bound of the 95% CI was greater than the protocol-specified noninferiority margin of −20%. Proportions of patients with breakthrough hemolysis were 4.0% (5 of 125 patients had 1 event each) in the ravulizumab group vs 10.7% (13 of 121 patients had a total of 15 events) in the eculizumab group (difference, −6.7% [95% CI, −14.21, 0.18]; Pinf < .0001). Hematology Am Soc Hematol Educ Program. 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%. Half-life of eculizumab is 11.25-17.25 days. 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. Data regarding packed red blood cell transfusions, incidence of MAVEs, and clinical manifestations of PNH are summarized in Table 3. 2020 Dec 10;11:599417. doi: 10.3389/fimmu.2020.599417. V. Ptushkin has received honoraria from Alexion Pharmaceuticals, Inc. 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). 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. BL, baseline (the last nonmissing assessment value before first dose of study drug). Prevention and treatment information (HHS). Other secondary efficacy outcomes at day 183. n = 119 patients were included in the analysis of clinical manifestations of PNH. Rituximab and eculizumab when treating nonmalignant hematologic disorders: infection risk, immunization recommendations, and antimicrobial prophylaxis needs. This site needs JavaScript to work properly. 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). A higher percentage of patients in the ravulizumab group experienced a ≥ 10-point improvement in the EORTC QLQ-C30 global health status/quality of life score (difference [95% CI], 4.8 [−7.7, 17.1]), physical functioning score (difference [95% CI], 3.7 [−8.7, 16.0]), and fatigue score (difference [95% CI], 9.1 [−2.5, 20.5]). Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. Jong Wook Lee, Flore Sicre de Fontbrune, Lily Wong Lee Lee, Viviani Pessoa, Sandra Gualandro, Wolfgang Füreder, Vadim Ptushkin, Scott T. Rottinghaus, Lori Volles, Lori Shafner, Rasha Aguzzi, Rajendra Pradhan, Hubert Schrezenmeier, Anita Hill; Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. None of these events was associated with inadequate terminal complement inhibition (free C5 levels ≥0.5 μg/mL). Conflict-of-interest disclosure: J.W.L. Overall, 73.4% and 65.5% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab … Pharmacodynamic analyses were performed on all patients who received ≥1 dose of study drug and had evaluable pharmacodynamic data. 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. 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. 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. View side-by-side comparisons of medication uses, ratings, cost, side effects and interactions. 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). 4 53.6% (95%CI 45.9–61.2%) in the ravulizumab … This event of mesenteric venous thrombosis with concurrent neutropenic colitis occurred in a patient who had history of aplastic anemia. Ravulizumab every 8 weeks is noninferior to eculizumab every 2 weeks across all efficacy end points in C5 inhibitor–naive PNH patients.

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