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Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies.
Blood Adv. 2018 09 11; 2(17):2176-2185.BA

Abstract

Ravulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (<234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201).

Authors+Show Affiliations

Department of Hematology, West German Cancer Center, University Hospital Essen, Essen, Germany.Alexion Pharmaceuticals, Inc, New Haven, CT.Department of Haematology, Leeds Teaching Hospitals, Leeds, United Kingdom.Alexion Pharmaceuticals, Inc, New Haven, CT.Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.Institute of Transfusion Medicine, University of Ulm, Ulm, Germany. Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen/University Hospital Ulm, Ulm, Germany.Clinical Immunology, Department of Internal Medicine, Centre Hospitalier Régional Universitaire de Lille-Hôpital Claude Huriez, Lille, France.Institute of Research Josep Carreras, Hospital Clinic Barcelona, Barcelona, Spain.Division of Medical Oncology and Haematology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.Department of Haematological Medicine, King's College Hospital, National Institute for Health Research and Wellcome King's Clinical Research Facility, London, United Kingdom.Department of Clinical Haematology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.Alexion Pharmaceuticals, Inc, Lexington, MA; and.Alexion Pharmaceuticals, Inc, New Haven, CT.Alexion Pharmaceuticals, Inc, New Haven, CT.Department of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30171081

Citation

Röth, Alexander, et al. "Ravulizumab (ALXN1210) in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results of 2 Phase 1b/2 Studies." Blood Advances, vol. 2, no. 17, 2018, pp. 2176-2185.
Röth A, Rottinghaus ST, Hill A, et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv. 2018;2(17):2176-2185.
Röth, A., Rottinghaus, S. T., Hill, A., Bachman, E. S., Kim, J. S., Schrezenmeier, H., Terriou, L., Urbano-Ispizua, Á., Wells, R. A., Jang, J. H., Kulasekararaj, A. G., Szer, J., Aguzzi, R., Damokosh, A. I., Shafner, L., & Lee, J. W. (2018). Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Advances, 2(17), 2176-2185. https://doi.org/10.1182/bloodadvances.2018020644
Röth A, et al. Ravulizumab (ALXN1210) in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results of 2 Phase 1b/2 Studies. Blood Adv. 2018 09 11;2(17):2176-2185. PubMed PMID: 30171081.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. AU - Röth,Alexander, AU - Rottinghaus,Scott T, AU - Hill,Anita, AU - Bachman,Eric S, AU - Kim,Jin Seok, AU - Schrezenmeier,Hubert, AU - Terriou,Louis, AU - Urbano-Ispizua,Álvaro, AU - Wells,Richard A, AU - Jang,Jun Ho, AU - Kulasekararaj,Austin G, AU - Szer,Jeff, AU - Aguzzi,Rasha, AU - Damokosh,Andrew I, AU - Shafner,Lori, AU - Lee,Jong Wook, PY - 2018/05/05/received PY - 2018/07/25/accepted PY - 2018/9/2/entrez PY - 2018/9/2/pubmed PY - 2019/8/29/medline SP - 2176 EP - 2185 JF - Blood advances JO - Blood Adv VL - 2 IS - 17 N2 - Ravulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (<234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201). SN - 2473-9537 UR - https://www.unboundmedicine.com/medline/citation/30171081/Ravulizumab__ALXN1210__in_patients_with_paroxysmal_nocturnal_hemoglobinuria:_results_of_2_phase_1b/2_studies_ L2 - https://ashpublications.org/bloodadvances/article-lookup/doi/10.1182/bloodadvances.2018020644 DB - PRIME DP - Unbound Medicine ER -