has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. E.B. C5a is a pro-in… Login with your ISN username and password. Normal range, 11.5 to 16.0 g/dL (women) and 13.0 to 17.5 g/dL (men). Demographic and baseline clinical characteristics, Erythrocytes with complete deficiency in glycosylphosphatidylinositol-anchored proteins, including complement regulatory proteins CD59 and CD55.30. Key exclusion criteria included LDH value >2× the ULN in the 6 months before day 1, major adverse vascular event (supplemental Appendix, section 2) within 6 months before day 1, platelet count 30 × 109/L, absolute neutrophil count <0.5 × 109/L, body weight <40 kg at screening, history of bone marrow transplantation, and history of N meningitidis infection (supplemental Appendix, section 2). The authors thank Lori Volles, Rodrigo Pavani, and Masayo Ogawa of Alexion Pharmaceuticals for their contribution to the implementation of the study. 21,22 Ravulizumab binds to C5 with high affinity and prevents hemolysis by inhibiting formation of C5a and C5b. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic … We use cookies to help provide and enhance our service and tailor content and ads. Ultomiris (ravulizumab) is expected to be more cost-effective than its predecessor Soliris (eculizumab) as a treatment for atypical hemolytic uremic syndrome (aHUS) in the U.S., a new study indicates.. Among 7 episodes of breakthrough hemolysis, 4 were associated with inadequate C5 inhibition, 2 were primarily associated with infection, and 1 was of unclear etiology. has received consultancies, honoraria, and research funding from Alexion, Novartis, and Pfizer and research funding from Amgen. have received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. All analyses were performed using SAS release (SAS Institute Inc., Cary, NC), version 9.4 or higher, or other validated statistical software. These results are qualitatively similar to those observed in patients naive to C5 inhibitor therapy,26 providing further evidence that ravulizumab provides complete inhibition of C5 to levels <0.5 μg/mL compared with eculizumab, which did not provide complete inhibition in all patients, and may mitigate the observed incidence and clinical sequelae of breakthrough hemolysis that has been observed with labeled-dose eculizumab.17-19. Medical writing and editorial support were provided by Lynn Brown and Traci Stuve of ApotheCom. Because noninferiority was achieved for the primary end point and all 4 key secondary end points, superiority testing of percentage change in LDH was performed. Post hoc P values were calculated for testing of noninferiority (Pinf) relative to the prespecified noninferiority margins to assess the strength of evidence of the study results. If noninferiority was established for all key secondary end points, then superiority was assessed via a closed-testing procedure, using a 2-sided 0.05 test for each parameter, in the following order: percentage change in LDH, FACIT-Fatigue, breakthrough hemolysis, stabilized hemoglobin, and transfusion avoidance (supplemental Appendix, section 2). Similarly, shifts in clinical manifestations of PNH were infrequent in both treatment groups, and no patient experienced a major adverse vascular event (Table 3). The key secondary end points were tested for noninferiority in a hierarchical manner provided that noninferiority was declared for the primary end point. 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%). Values are reported as n (%) of patients. Ravulizumab (ALXN1210) vs eculizumab … The study, “ A US cost-minimization model comparing ravulizumab versus eculizumab for the treatment of atypical hemolytic uremic … Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Pyrexia and hemolysis were the only serious adverse events reported by >1 patient (3 and 2 patients, respectively, all in the eculizumab group). Correspondence: Austin G. Kulasekararaj, Department of Haematological Medicine, King’s College Hospital, NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom; e-mail: austin.kulasekararaj@nhs.net. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. (A-B) A gyros-based fluorescence assay was used for patients who received ravulizumab (A), and an electrochemiluminescence immunoassay was used for patients who received eculizumab (B). The study enrolled adult patients (≥18 years of age) who had documented diagnoses of PNH, confirmed by high-sensitivity flow cytometry evaluation of red blood cells and white blood cells with granulocyte or monocyte clone size of ≥5% and who were clinically stable on eculizumab treatment. Four patients discontinued the study, 1 in the ravulizumab group (patient decision) and 3 in the eculizumab group (patient decision, lack of efficacy, and pregnancy; n = 1 for each). Ravulizumab and eculizumab were well tolerated in this study. Ravulizumab for treating atypical haemolytic uraemic syndrome (aHUS) [ID1530] By continuing you agree to the Use of Cookies. Patients were stratified according to transfusion history and were randomly assigned (1:1) to 26 weeks of open-label treatment with IV ravulizumab or eculizumab. The aHUS-311 study is an Alexion-sponsored, phase 3, single-arm trial designed to investigate the effects of ravulizumab … Clinical trial recommendations for potential Alport syndrome therapies. In aHUS, mutations in complement pathway genes, such as CFH, MCP (CD46), and CFI, lead to the uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy (TMA)or blood clots in small blood vessels. Is ravulizumab the new treatment of choice for atypical hemolytic uremic syndrome (aHUS)? There were no treatment-emergent antidrug antibodies in patients treated with ravulizumab. Most likely aHUS patients would say the same about their quality of life improvement from fewer infusions. The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. This study was performed in accordance with the principles of the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. Mean (95% CI) free C5 levels in the ravulizumab and eculizumab groups over time. The target of ravulizumab-cwvz is the same eculizumab (Soliris) with changes … Contribution: A.G.K., A.H., J.S., and S.N. If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (Pinf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), −0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, −8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, −0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, −4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, −10.41 to 13.31]). In December 2018 it was given an early approval ( Alexion playing a “rare disease priority review … The primary efficacy end point of percentage change in LDH from baseline to day 183 was analyzed by mixed model for repeated measures with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction as well as the fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cell transfusion history. Key secondary efficacy end points were proportion of patients with breakthrough hemolysis, defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2× the ULN after prior reduction of LDH to <1.5× the ULN on treatment; change from baseline in quality of life, assessed with the FACIT-Fatigue Scale Version 4.0; transfusion avoidance, defined as the proportion of patients who remained transfusion free and did not require a transfusion per protocol-specified guidelines; 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. This material is provided for educational purposes only … Although an increased risk of meningococcal infections has been reported in recipients of complement inhibitor therapy,13,14,28,29 no such infections were observed in the present trial. Elsevier journal websites will be undergoing maintenance on Monday March 15 from 3:00 am to 5:00 pm US Eastern. Ravulizumab, a new long-acting C5 inhibitor, recently received FDA approval for the Until additional data/analyses are available, eculizumab remains the drug of choice for an acute aHUS episode, whereas ravulizumab has several advantages in maintenance treatment. For FACIT-Fatigue, Diff (95% CI) was based on estimated difference in change from baseline with 95% CI. By continuing you agree to the, https://doi.org/10.1016/j.kint.2020.03.011. Ultomiris (ravulizumab-cwvz) is used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and hemolytic uremic syndrome. Ravulizumab every 8 weeks is noninferior to eculizumab every 2 weeks across all efficacy end points in eculizumab-experienced PNH patients. Atypical and secondary haemolytic uremic syndromes have a distinct presentation and no common genetic risk factors. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. © 2020 International Society of Nephrology. (B) Secondary end point. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). No meningococcal infections or discontinuations due to adverse events occurred. At the end of the 26-week treatment period, ravulizumab-treated patients continued weight-based maintenance dosing of ravulizumab, whereas eculizumab-treated patients were switched to open-label ravulizumab for the extension period. S.T.R., L.S., A.I.D., and S.O. This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. Aims: Ravulizumab, engineered from eculizumab, provides sustained C5 inhibition in atypical hemolytic uremic syndrome (aHUS) … Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. Twelve patients experienced serious adverse events (4 ravulizumab patients and 8 eculizumab patients). Ravulizumab (ALXN1210) is a new complement component 5 (C5) inhibitor that produces immediate, complete, and sustained inhibition of C5 with an extended, 8-week dosing interval. Baseline (BL) is defined as the last nonmissing value before first dose of study drug. Statistical analysis, pharmacokinetic and pharmacodyamic assessments, and editorial review were provided by Rasha Aguzzi, Rajendra Pradhan, and Stephan Ortiz of Alexion Pharmaceuticals. No adverse events led to withdrawal of study drug during the randomized treatment period. has received consultancies, honoraria, and advisory board membership for Alexion Pharmaceuticals, Inc. A.R. Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany. Qualified academic investigators may request participant-level, de-identified clinical data and supporting documents (statistical analysis plan and protocol) pertaining to this study. Treatment with ravulizumab also achieved noninferiority compared with eculizumab for all 4 key secondary end points, with all point estimates for treatment difference favoring ravulizumab (Figure 1B; Table 2). No patients in the ravulizumab group experienced breakthrough hemolysis compared with 5 (5.1%) patients in the eculizumab group (difference, 5.1% [95% CI, −8.89% to 18.99%, Pinf < .0004). Copyright © 2021 Elsevier Inc. except certain content provided by third parties. are employees and stockholders of Alexion Pharmaceuticals, Inc. J.W.L. Percentage of patients achieving LDH normalization over time in the ravulizumab and eculizumab treatment groups. It is a Complement inhibitor too. The complete and sustained C5 inhibition associated with ravulizumab may account for the consistent results across end points. Ravulizumab’s brand name is “Ultomiris” , as “Soliris” is for eculizumab. 1 Last year, ravulizumab (Ultomiris), a long-acting C5 inhibitor derived from eculizumab, received FDA and EMEA approval for the treatment of patients with paroxysmal nocturnal hematuria (PNH). Ravulizumab provided immediate, complete, and sustained inhibition … For stable patients receiving label-dose eculizumab therapy, providing an effective treatment duration that is 4 times longer between infusions by switching to ravulizumab given every 8 weeks is likely to result in a substantially reduced burden of treatment, fewer occurrences of breakthrough hemolysis and their clinical consequences, better quality of life, and greater likelihood of retention on long-term therapy. doi: https://doi.org/10.1182/blood-2018-09-876805. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. This 26-week, active-controlled study of 195 patients with PNH who were clinically stable on labeled-dose eculizumab treatment for a mean for 5.8 years demonstrated that ravulizumab administered every 8 weeks effectively inhibited complement-mediated hemolysis and had a safety profile similar to that of eculizumab.5-7 Ravulizumab met the primary end point (percentage change in LDH from baseline to day 183) and all key secondary end points, showing noninferiority to biweekly treatment with 900 mg eculizumab, the current standard of care for PNH.13,14 Point estimates consistently favored ravulizumab treatment over eculizumab treatment for the primary end point and all 4 key secondary efficacy end points, although none of the results from this noninferiority trial demonstrated superiority. There were no deaths and no cases of meningococcal infection. Until additional data/analyses are available, eculizumab remains the drug of choice Soliris is also used to treat atypical … The alternative complement pathway is characterized by the cleavage of the complement protein C5into C5a and C5b fragments. Moreover, no major adverse vascular events were observed in either treatment group. Patients randomly assigned to the ravulizumab treatment group received weight-based dosing: a loading dose on day 1 followed by maintenance doses of ravulizumab (on day 15 and every 8 weeks thereafter) (supplemental Appendix, section 2; supplemental Figure 1). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). Ravulizumab-cwvz (Ultomiris) is a second generation monoclonal antibody for aHUS made by Alexion pharmaceuticals, Inc. 14 As previously described, eculizumab binds to the complement protein C5 in the intravascular space. Patient demographics and baseline clinical characteristics were well balanced between treatment groups (Table 1). Ultomiris information includes side effects, … Additionally, 2 events with complete C5 inhibition were associated with infection. Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complementpathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) andsevere end-organ damage. developed the protocol, recruited patients, collected data, analyzed and interpreted the data, contributed to the manuscript, and approved the final version. All received meningococcal vaccination if they had not received it in the past 3 years. 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%. You will then receive an email that contains a secure link for resetting your password, If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password, DOI: https://doi.org/10.1016/j.kint.2020.03.011. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. Two patients withdrew before receiving study drug, and 195 received treatment (ravulizumab, n = 97; eculizumab, n = 98) (supplemental Appendix, section 3; supplemental Figure 2). Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, transfusion avoidance, and stabilized hemoglobin. We apologize for the inconvenience. Eighty-five of 97 patients (87.6%) receiving ravulizumab and 81 of 98 patients (82.7%) receiving eculizumab avoided transfusion, with a between-group difference of 5.5% (95% CI, −4.27% to 15.68%, Pinf < .0001), whereas 74 of 97 patients (76.3%) receiving ravulizumab and 74 of 98 patients (75.5%) receiving eculizumab achieved stabilized hemoglobin levels (difference, 1.4% [95% CI, −10.41% to 13.31%], Pinf < .0005). Ravulizumab achieved noninferiority compared with eculizumab (Figure 1A; Table 2) for the primary end point of percentage change in LDH, with the point estimate for treatment difference favoring ravulizumab. Of these 5 patients with breakthrough hemolysis, 4 had 1 event each and 1 had 3 events, the third of which resulted in hospitalization and subsequent study discontinuation because of lack of efficacy (this patient subsequently received eculizumab 1200 mg every 2 weeks). The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. Efficacy analyses were performed on the full analysis set (all patients who received at least 1 dose of ravulizumab or eculizumab). Other secondary efficacy outcomes at day 183. has received consultancies and honoraria from Alexion, Roche, and Novartis and research funding from Alexion and Roche. With ULTOMIRIS, you can experience the freedom of up to 8 weeks between infusions a, with the comfort of established safety.Whether you or a child you care for had a recent atypical-HUS diagnosis, or you’ve been part of the atypical-HUS … recruited patients, collected data, analyzed and interpreted the data, contributed to the manuscript, and approved the final version; S.T.R., A.I.D., S.O., and L.S., developed the protocol, analyzed and interpreted the data, contributed to the manuscript, and approved the final version; S.L., R.W., A.G., J.W.L., E.O.G., C.I.P., and A.R. (%), LDH, least squares mean % change (95% CI), Difference in percentage change from baseline, FACIT-Fatigue score, least squares mean change (95% CI), Total number of packed red blood cell units transfused, mean (SD), Patients with major adverse vascular events, n (%), Patients with adverse events leading to withdrawal of study drug, Patients with serious adverse events leading to withdrawal of study drug. To read this article in full you will need to make a payment. Long-term ACE inhibition in Alport syndrome: are the benefits worth the risks? The planned sample size of ∼192 enrolled patients provided 90% power to demonstrate noninferiority of ravulizumab to eculizumab at a 1-sided α level of 0.025, a 10% dropout rate, and a noninferiority margin of 15% for percentage change in LDH from baseline to day 183. Blood 2019; 133 (6): 540–549. Like the first-generation C5 inhibitor, eculizumab, ravulizumab … (%), Time from PNH diagnosis to consent, mean (SD), y, History of major adverse vascular events, no. for an acute aHUS episode, whereas ravulizumab has several advantages in maintenance The publication costs of this article were defrayed in part by page charge payment. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. Patients randomly assigned to the eculizumab treatment group received 900 mg every 2 weeks. Eculizumab-treated patients received a weight-based loading dose of ravulizumab followed 2 weeks later by weight-based maintenance doses every 8 weeks. BOSTON -- (BUSINESS WIRE)--May 1, 2020-- Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) today announced that the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending marketing authorization in the European Union for ULTOMIRIS ® (ravulizumab) for the treatment of patients with a body weight of 10 kg or above with atypical hemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received SOLIRIS ® (eculizumab… Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Horizontal line indicates free C5 level of 0.5 µg/mL. Least-squares mean (standard error) change in FACIT-Fatigue total score was 2.01 (0.697) in the ravulizumab group and 0.54 (0.704) in the eculizumab group (difference, 1.47 [95% CI, −0.21 to 3.15], Pinf < .0001). Once this occurs, the resulting eculizumab… The least-squares estimate of the mean (standard error) in percentage change in LDH from baseline to day 183 showed a decrease of 0.82% (3.033%) for the ravulizumab group and an increase of 8.39% (3.041%) for the eculizumab group, with a treatment difference (ravulizumab − eculizumab) of 9.21% (95% CI, −0.42% to 18.84%). Ravulizumab was designed to address the limitations in eculizumab therapy, particularly eculizumab’s short half-life and frequent dosing schedule. Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. Safety analyses were performed on the safety set, defined as all patients who received at least 1 dose of ravulizumab or eculizumab. Eligible patients must have received eculizumab treatment of ≥6 months at labeled dose before study entry, had an LDH level ≤1.5× the upper limit of normal (ULN; 246 U/L) at screening, and been vaccinated against Neisseria meningitidis <3 years before dosing or at the time of study drug initiation to reduce the risk of meningococcal infections. ALXN1210-PNH-302 was a multicenter, randomized, open-label, active-controlled study conducted in 49 centers in 11 countries (registered at www.clinicaltrials.gov as #NCT03056040 and EudraCT as #2016-002026-36, CHAMPION 302). Antidrug antibodies were also assessed. The most frequently reported adverse event occurring in 3% or more of patients in either treatment group was headache, which occurred in 26.8% of patients treated with ravulizumab and in 17.3% of patients treated with eculizumab. If at any point noninferiority or superiority was not reached, then all subsequent tests were stopped. Baseline was defined as the last nonmissing value before the first dose of study drug. As expected in a patient population that was clinically stable on eculizumab therapy, the proportion of patients who achieved normalization in LDH was relatively stable over time. LDH normalization is defined as proportion of patients who achieved LDH level ≤1× the ULN (246 U/L). Primary and key secondary efficacy outcomes at day 183. The mean (standard deviation [SD]) total number of packed red blood cell units transfused during the treatment period was comparable in the ravulizumab (4.3 [4.76]) and eculizumab (3.4 [3.01]) treatment groups (Table 3). Four of the 7 breakthrough hemolysis events were associated with time-matched free C5 ≥ 0.5 μg/mL, a level associated with incomplete inhibition of hemolysis.13,14 One of these was also associated with infection. … Treatment effect. 2019;133(6):530-539. The sponsor and investigators thank the patients and their families for their participation in, and support for, this clinical study. R.P.d.L. The serious infections noted in this study resolved without sequelae. Society Members, full access to the journal is a member benefit. study were able to stop dialysis, probably due to differences in the study populations. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS … An overview of adverse events is shown in Table 4. Ravulizumab-cwvz (Ultomiris, Alexion) received FDA approval for the treatment of atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA) for adult and pediatric patients. Day 29, 43, 57, 85, 99, 113, 141, 155, and 169 data are from anytime for the ravulizumab group and predose for the eculizumab group. No sensitive subgroups were identified. A difference in percentage change in LDH from baseline to day 183 between ravulizumab and eculizumab treatment groups along with a 2-sided 95% confidence interval (CI) were calculated. Ultomiris (ravulizumab-cwvz) and Soliris (eculizumab) are monoclonal antibodies used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH). Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. This is ravulizumab … A conclusion of noninferiority indicates that the noninferiority margin is larger or smaller than the lower or upper bound of the 95% CI indicated in boldface. Both ravulizumab and eculizumab dramatically improved the platelet count after 1 week. n = 50 male patients in the ravulizumab group and n = 48 male patients in the eculizumab group. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab every 2 weeks to ravulizumab every 8 weeks. We use cookies to help provide and enhance our service and tailor content and ads. Testing of the noninferiority hypothesis is assessed by comparing the bolded limit of the 95% CI to the noninferiority margin. Of the 195 patients who received treatment, 191 completed the 26-week treatment period (ravulizumab, n = 96; eculizumab, n = 95). If you already have an account, you can login, however profile updates, purchases and subscription activations will be disabled until after the upgrade. Serious infections occurred in 2 patients (2.1%) in the ravulizumab group (influenza and lower respiratory tract infection [without positive culture]) and in 1 eculizumab-treated patient (1.0%) (acute pyelonephritis [causative agent unknown]). Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. Adverse events were recorded by type, incidence, and severity. Similarly, mean LDH values were within the normal range at baseline and generally sustained over time (supplemental Appendix, section 3; supplemental Figure 3). Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. A US cost-minimization model comparing ravulizumab versus eculizumab for the treatment of atypical hemolytic uremic syndrome. Results of phase 1b/2 studies in complement-inhibitor–naive patients with PNH demonstrate that ravulizumab provides rapid and sustained reduction in complement-mediated hemolysis at dosing intervals up to 12 weeks and overall improvement of PNH-related symptomatology and quality of life.25 In the largest phase 3 study in complement-inhibitor–naive PNH patients conducted to date, ravulizumab was shown to be noninferior to eculizumab for all end points, including transfusion avoidance, lactate dehydrogenase (LDH) normalization, percentage change in LDH levels, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, breakthrough hemolysis, and hemoglobin stabilization.26 In this phase 3 study, we assessed the noninferiority of ravulizumab vs eculizumab in patients with PNH on stable eculizumab therapy. Ravulizumab (ravulizumab-cwvz; ULTOMIRIS™), a humanized monoclonal antibody, is a complement C5 inhibitor developed by Alexion Pharmaceuticals for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS). Although LDH levels increased by 8.4% in the eculizumab group and decreased 0.82% in the ravulizumab group at day 183, the difference did not reach statistical significance for superiority (P = .058). 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. All patients who received treatment (100%) received all planned infusions of study medication. One breakthrough hemolysis event was of unknown etiology. Editorial review was provided by Kenneth Pomerantz of Alexion Pharmaceuticals, Inc. The red triangle indicates the noninferiority margin. A safety review committee monitored safety, and an independent data monitoring committee monitored data for cases of meningococcal infection. Search for other works by this author on: Atypical hemolytic uremic syndrome: a brief review, Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms, The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria, Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria, Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria, Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome, Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies, Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome, Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: A single-arm, open-label trial, Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study, Soliris [summary of product characteristics], 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, Thrombosis in paroxysmal nocturnal hemoglobinuria, Eculizumab dosing intervals longer than 17 days may be associated with greater risk of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria, Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab, Development of a disease-specific quality of life questionnaire for patients with aplastic anemia and/or paroxysmal nocturnal hemoglobinuria (QLQ-AA/PNH)-report on phases I and II, 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, 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], Optimization of dose regimen for ALXN1210, a novel complement C5 inhibitor, in patients with paroxysmal nocturnal hemoglobinuria (PNH): Results of 2 phase 1/2 studies [abstract], Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study, Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria, High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine, Interim analysis of safety outcomes during treatment with eculizumab: results from the International Paroxysmal Nocturnal Hemoglobinuria Registry [abstract], Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents, © 2019 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, https://doi.org/10.1182/blood-2018-09-876805, Ravulizumab: a complementary option for PNH, Age at first infusion of study drug, mean (SD), y, Years on eculizumab before first study infusion, Patients with packed red blood cells/whole blood transfusions received within 1 y before first dose, no.
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