Epub 2021 Feb 5. Reported adverse events from the ravulizumab phase III clinical trials.38,39. Myasthenia gravis (MG) is a common autoimmune disorder of the neuromuscular junctions. Confirmatory development study with rozanolixizumab in patients with myasthenia gravis to start in H2 2019 Brussels, Belgium – 18 October 2018, 7:00 AM CEST – UCB today announced positive results from a phase 2 … Members of _ can log in with their society credentials below, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USAHarvard Medical School, Boston, MA, USA, Hematology Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. For precertification of ravulizumab-cwvz, call (866) 752-7021, or fax (866) 267-3277. Epub 2019 May 22. 2. The initial phase 2 trial (NCT00727194), sponsored by Alexion Pharmaceuticals, was a prospective, double-blind, placebo-controlled crossover design of 14 AChR+, gMG treatment-refractory patients [Myasthenia Gravis … At the current time, ravulizumab is too new for any long-term data assessing safety or efficacy. Following treatment with eculizumab, the trial participants were found to have a decrease in lactate dehydrogenase levels (LDH) from a mean of 3111 ± 598 IU/l pre-enrollment to a mean of 594 ± 32 IU/l during treatment (p = 0.002). All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement. Clipboard, Search History, and several other advanced features are temporarily unavailable. There are also no data to determine whether ravulizumab will be as well-tolerated and effective as eculizumab in special populations with PNH, including pregnant woman or children. Values are mean ±…, National Library of Medicine The endosomal degradation of eculizumab only occurs when eculizumab is associated with C5. Open Label use (no placebo) of Ravulizumab … View or download all the content the society has access to. Alexion has paused further enrollment in the Phase 2 study of ALXN2050 monotherapy in PNH patients, pending the receipt of further Phase 1 data (expected in the second quarter of 2021) that will allow for dose escalation in the Phase 2 … Therefore, blocking C5 to prevent the conversion of C5 to C5a and C5b would effectively stop the complement cascade regardless of the stimulus.26 In addition, C5 blockade is downstream in the pathway so as not to impair the immunoprotective and immunoregulatory functions of C3b-mediated opsonization and immune complex clearance.13, Once C5 was identified as an optimal target, panels of murine antihuman C5 monoclonal antibodies were created and screened for their ability both to inhibit complement-mediated lysis and to effectively block the generation of C5a.13 From these panels, a single monoclonal antibody emerged. At the time of enrollment, all participants were found to have mean baseline free hemoglobin levels and reticulocyte counts above the upper limit of normal and to have a mean plasma haptoglobin below the upper limit of normal. In both studies, the assessed endpoints were similar. Only blood sampling at visits 9–16. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder that is characterized by hemolytic anemia, bone marrow failure and thrombosis. For the key secondary endpoints, mean free hemoglobin levels decreased for all but one treatment cohort, while all cohorts had an improvement in total hemoglobin and a decrease in symptom burden. There was one reported case of an alpha-hemolytic streptococcal bacteremia and no reported meningococcal infections. Affiliations. Once again, no meningococcal infections occurred in either treatment group, but two participants had serious infections on ravulizumab and one participant had a serious infection on eculizumab. Phase 3 development of intravenous ravulizumab for the treatment of aHUS is underway worldwide. Ravulizumab was once again found to be non-inferior to eculizumab for the primary endpoint (Table 1). The primary efficacy endpoint of the 302 study was hemolysis, as measured by a percentage change in LDH levels from baseline to day 183. The primary adverse event in both studies was headache, occurring in 43.6% of participants, while two participants in the phase IIb study developed sepsis secondary to meningococcal infection. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry, Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays, Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan, Paroxysmal nocturnal haemoglobinuria: clinical manifestations, haematology, and nature of the disease, Baseline characteristics and disease burden in patients in the international paroxysmal nocturnal hemoglobinuria registry, Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria, Natural history of paroxysmal nocturnal hemoglobinuria, Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors, Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories, Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival, Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria, Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action, FDA approves ravulizumab-cwvz for paroxysmal nocturnal hemoglobinuria, Prescribing information: Soliris (eculizumab), Prescribing information: Ultomiris (ravulizumab), Ravulizumab: a complementary option for PNH, Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria, The complement-inhibitory activity of CD59 residents in its capacity to block incorporation of C9 into membrane C5b-9, Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria, Diagnosis and management of paroxysmal nocturnal hemoglobinuria, Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv, Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria, The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria, Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria, Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria, Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria, 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, When the patient is a gold mine: the trouble with rare-disease drugs, Opportunity cost of funding drugs for rare diseases: the cost-effectiveness of eculizumab in paroxysmal nocturnal hemoglobinuria, Genetic variants in C5 and poor response to eculizumab, 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, Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies, Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study, Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study, Ultomiris (ravulizumab-cwvz) – New orphan drug approval, Single-arm study of ALXN1210 in complement inhibitor treatment-naïve adult and adolescent patients with atypical hemolytic uremic syndrome (aHUS), Study of ALXN1210 in children and adolescents with atypical hemolytic uremic syndrome (aHUS), Search of: recruiting, active, not recruiting, completed studies | Paroxysmal nocturnal hemoglobinuria, APL-2, a Complement C3 inhibitor for the potential treatment of paroxysmal nocturnal hemoglobinuria (PNH): phase I data from two completed studies in healthy volunteers, The SMART-IgG Anti-hC5 antibody (SKY59/RO7112689) has favorable PK, PD, subcutaneous bioavailability, and safety profile in phase I HV study, SAGE Publications Ltd unless otherwise noted. Epub 2018 Jul 24. You can be signed in via any or all of the methods shown below at the same time. 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. Front Neurol. The use of ravulizumab in myasthenia gravis and IgA nephropathy is also being evaluated in the USA in early-phase … Background: Rozanolixizumab is an SC anti-FcRn monoclonal antibody designed … CD55 accelerates the rate of destruction of membrane-bound C3 convertase while CD59 blocks the formation of the MAC. Eculizumab was administered according to its approved dosing schedule. Based on the results of the TRIUMPH study, as well as the prespecified interim 26-week analysis of the SHEPHERD study, eculizumab was granted US FDA approval in March 2007 and European Medicines Agency approval in June 2007.8 Subsequent studies have demonstrated eculizumab’s long-term efficacy and safety. Schematic design of the phase 2 study of efgartigimod in patients with generalized…, (A) Serum levels of efgartigimod. Moving forward, ravulizumab will likely have expanded indications. Objective: Report results from a Phase 2a study of rozanolixizumab in patients with GMG ([NCT03052751][1]). Up to 50% of patients experience headache following the first dose of eculizumab and approximately 0.5% of patients per year will develop meningococcal infection while on the therapy.20,31 In addition, eculizumab’s half-life of approximately 11 days necessitates indefinite intravenous dosing of eculizumab every 2 weeks.12 This dosing schedule is burdensome for patients and has been shown to cause psychosocial strain for patients with PNH both in their relationships with friends and family and in their ability to function in the workplace.32 Moreover, despite eculizumab infusions every 14 days, a small percentage of patients with PNH may experience fatigue and breakthrough hemolysis due to insufficient complement inhibition in the final 24–48 h before their next infusion.20,31 Due to breakthrough hemolysis, as well as opson-mediated extravascular hemolysis and bone marrow failure, 25–35% of patients on eculizumab therapy continue to require red cell transfusions.20, The frequent and indefinite need for eculizumab dosing also plays a role in the high cost of eculizumab therapy. Overview of number of patients screened and randomized over the efgartigimod and placebo treatment arms. This site uses cookies. Ulrichts P, Guglietta A, Dreier T, van Bragt T, Hanssens V, Hofman E, Vankerckhoven B, Verheesen P, Ongenae N, Lykhopiy V, Enriquez FJ, Cho J, Ober RJ, Ward ES, de Haard H, Leupin N. J Clin Invest. Epub 2017 Oct 20. Values are individual values expressed relative (%) to the respective individual anti-AChR autoantibody concentrations immediately prior to first dose at visit 1; the anti-AChR autoantibody levels of patient 3 were below the limit of quantification. The two phase III studies of ravulizumab in complement-inhibitor-naïve patients with atypical hemolytic uremic syndrome are underway.41,42 In addition, ravulizumab is currently being tested in clinical trials for children and adolescents with PNH and atypical hemolytic uremic syndrome and for adults with myasthenia gravis and immunoglobulin A nephropathy.15 A subcutaneous formulation of ravulizumab is also under development to further improve ease of ravulizumab administration.15. Please enable it to take advantage of the complete set of features! In the alternative pathway of complement activation, C3 spontaneously hydrolyzes leading to the creation of C3 convertase (C3 convertase can also be formed through the lectin and classical pathways of complement). 2021 Jan 27;14:1756286420986747. doi: 10.1177/1756286420986747. If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Ravulizumab was found to have a half-life of 32 days and to have a low intersubject variability in PK parameters. To increase eculizumab’s half-life, two changes were made to the antibody. Ravulizumab and eculizumab dosing were the same as in the 301 study. Su S, Liu Q, Zhang X, Wen X, Lei L, Shen F, Fan Z, Duo J, Lu Y, Di L, Wang M, Chen H, Zhu W, Xu M, Wang S, Da Y. Ther Adv Neurol Disord. FundingThe author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iDsRobert M. Stern https://orcid.org/0000-0001-7693-7738, Nathan T. Connell https://orcid.org/0000-0003-4100-7826. 2019 Nov;31(6):623-633. doi: 10.1097/BOR.0000000000000647. Adverse events were similar between the two arms. Bethesda, MD 20894, Copyright Accessibility Consistent with this, the median number of transfused red blood cell units in the eculizumab group was 0 compared with 10 in the placebo group (p < 0.001). Secondary endpoints included LDH levels and quality of life measures. Investigational antibody rozanolixizumab has proven safe and effective in treating symptoms associated with myasthenia gravis (MG), Phase 2 results show.. Based on the results of the MG0002 Phase 2 … A total of two patients also experienced new thrombotic events, the first while on eculizumab therapy and the second 1 month following completion of eculizumab. In addition, in all participants, levels of C5 were reduced by >99%. The first study, the 301 study (ClinicalTrials.gov identifier: NCT02946463), assessed the non-inferiority of ravulizumab compared with eculizumab in adult patients with PNH naïve to complement inhibitors.38 The second study, the 302 study (ClinicalTrials.gov identifier: NCT03056040), assessed the non-inferiority of ravulizumab compared with eculizumab in adult patients with PNH who had previously been treated with a C5 inhibitor.39 Both studies were conducted across more than 40 centers and in 10 countries and were published in February 2019. Please read and accept the terms and conditions and check the box to generate a sharing link. Most headaches were classified as mild to moderate in severity and were limited to the first 2 weeks of therapy. In all patients, this decrease in LDH occurred after a single dose of eculizumab. The e-mail addresses that you supply to use this service will not be used for any other purpose without your consent. The primary clinical manifestations of PNH include anemia, thrombosis, smooth muscle dystonia, chronic kidney disease, hemoglobinuria and bone marrow failure.9,19,25 These clinical findings arise from both complement-mediated hemolysis and deficiencies in GPI-linked proteins. In a phase 2 trial, 44 patients with generalized myasthenia gravis received daily subcutaneous injection of either 0.3 mg/kg zilucoplan, 0.1 mg/kg zilucoplan or placebo over 12 weeks . Sustained improvements in hemolytic markers and prolonged increases in patient-reported quality of life measures have also been observed.12,20, Recent studies have also demonstrated the safety and efficacy of eculizumab for specialized populations with PNH, including pregnant women and children.29,30 In a retrospective study of 75 pregnancies in 61 women treated with eculizumab for PNH during their pregnancies, there were no maternal deaths reported and only three fetal deaths. Ravulizumab, which is administered every 8 weeks versus every 2 weeks for eculizumab, has already gained approval for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), and Alexion is studying the drug in patient with myasthenia gravis … Lancet Neurol. Sharing links are not available for this article. In addition to the decline in LDH, patients were also found to have statistically significant improvements in global health and physical, emotional and cognitive functioning, as well as a statistically significant decrease in the need for red cell transfusions. Efgartigimod: A novel antibody depletion therapy in myasthenia gravis. What are some of the study details? 10,11 Headache was a notable side effect of rozanolixizumab. Myasthenia Gravis: A Multicenter, Randomized, Investigator- and Subject-Blind, Placebo-Controlled, Treatment Sequence Study Evaluating the Safety, Tolerability, and Efficacy of UCB7665 in Subjects With Moderate to Severe My… *Statistically significant change from baseline (. Until recently, the complement inhibitor, eculizumab, was the only United States Food and Drug Administration (US FDA)-approved therapy for the treatment of PNH. Values are mean ± standard error, and are expressed relative (%) to the respective IgG concentrations immediately prior to first dose at visit 1. 2017 Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1. Inclusion criteria in the 302 study included eculizumab treatment for ⩾6 months before study entry, baseline LDH ⩽1.5 times the upper limit of normal and documented meningococcal vaccination. Outcome Measures in Clinical Trials of Patients With Myasthenia Gravis. In 2017, with a cost of nearly US$18,000 per infusion in the United States, this amounts to an annual cost of nearly US$500,000 per patient with PNH.33 A cost-effectiveness analysis of eculizumab for the treatment of PNH conducted in Canada in 2014 demonstrated that when compared with supportive therapies, eculizumab resulted in an incremental cost per life-year of CAN$4.62 million, and a cost per quality-adjusted life-year of CAN$2.13 million. The mean LDH reduction ranged from 72.9% to 89.6% in the cohorts. No patients experienced meningococcal infections. All participants received prophylactic penicillin V and were followed up for a total of 150 days. After being given priority review and orphan drug status by the US FDA, ravulizumab was officially granted approval as the second drug for adult patients with PNH on 21 December 2018.16 While the estimated annual average cost of ravulizumab is still exceedingly high at approximately US$458,000, it is about 10% lower than the annual cost of eculizumab.40. Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis. Long-term safety data are especially important, given that ravulizumab carries a black box warning for serious meningococcal infection based on the two patients in the phase II study who developed meningococcal infections. Key secondary endpoints included the proportion of participants with breakthrough hemolysis, change from baseline in quality of life, transfusion avoidance and the proportion of participants with a stabilized hemoglobin. This alteration in just four amino acid residues generates a new antibody, ravulizumab, with a half-life three to four times longer than eculizumab.14,36. A phase 3 study (REGAIN study) reported significant improvement of MG‐QOL15 and QMG scores: Ravulizumab: C5 monoclonal antibody: Same as eculizumab, but long‐acting: A phase 3 study is in pipeline: Efgartigimod: FcRn monoclonal antibody: Reduction in pathogenic autoantibodies with IgG isotypes: A phase 2 …