PMID- 36272026 OWN - NLM STAT- MEDLINE DCOM- 20230308 LR - 20230308 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 40 IP - 1 DP - 2023 Jan TI - Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up. PG - 211-232 LID - 10.1007/s12325-022-02339-3 [doi] AB - INTRODUCTION: This study compared the pharmacokinetics (PK) of the ravulizumab on-body delivery system for subcutaneous (SUBQ) administration with intravenous (IV) ravulizumab in eculizumab-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: Patients with PNH received SUBQ ravulizumab (n = 90) or IV ravulizumab (n = 46) during the 10-week randomized treatment period; all patients then received SUBQ ravulizumab during an extension period (< 172 weeks; data cutoff 1 year). Primary endpoint was day 71 serum ravulizumab trough concentration (C(trough)). Secondary endpoints were ravulizumab C(trough) and free C5 over time. Efficacy endpoints included change in lactate dehydrogenase (LDH), breakthrough hemolysis (BTH), transfusion avoidance, stabilized hemoglobin, and Treatment Administration Satisfaction Questionnaire (TASQ) score. Safety, including adverse events (AEs) and adverse device effects (ADEs), was assessed until data cutoff. RESULTS: SUBQ ravulizumab demonstrated PK non-inferiority with IV ravulizumab (day 71 SUBQ/IV geometric least-squares means ratio 1.257 [90% confidence interval 1.160-1.361; p < 0.0001]). Through 1 year of SUBQ administration, ravulizumab C(trough) values were > 175 mug/mL (PK threshold) and free C5 < 0.5 mug/mL (PD threshold). Efficacy endpoints remained stable: mean (standard deviation, SD) LDH percentage change was 0.9% (20.5%); BTH events, 5/128 patients (3.9%); 83.6% achieved transfusion avoidance; 79.7% achieved stabilized hemoglobin. Total TASQ score showed improved satisfaction with SUBQ ravulizumab compared with IV eculizumab (mean [SD] change at SUBQ day 351, - 69.3 [80.1]). The most common AEs during SUBQ treatment (excluding ADEs) were headache (14.1%), COVID-19 (14.1%), and pyrexia (10.9%); the most common ADE unrelated to a device product issue was injection site reaction (4.7%). Although many patients had >/= 1 device issue-related ADE, full SUBQ dose administration was achieved in 99.9% of attempts. CONCLUSIONS: SUBQ ravulizumab provides an additional treatment choice for patients with PNH. Patients may switch to SUBQ ravulizumab from IV eculizumab or ravulizumab without loss of efficacy. TRIAL REGISTRATION: NCT03748823. CI - (c) 2022. The Author(s). FAU - Yenerel, Mustafa N AU - Yenerel MN AUID- ORCID: 0000-0002-6473-1342 AD - Division of Hematology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. mnyenerel@gmail.com. FAU - Sicre de Fontbrune, Flore AU - Sicre de Fontbrune F AD - Hematology and Bone Marrow Transplant Unit, Assistance Publique Hopitaux des Paris, Saint Louis Hospital, Paris, France. FAU - Piatek, Caroline AU - Piatek C AD - Jane Anne Nohl Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. FAU - Sahin, Fahri AU - Sahin F AD - Division of Hematology, Department of Internal Medicine, Ege University, Izmir, Turkey. FAU - Fureder, Wolfgang AU - Fureder W AD - Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria. FAU - Ortiz, Stephan AU - Ortiz S AD - Alexion, AstraZeneca Rare Disease, Boston, MA, USA. FAU - Ogawa, Masayo AU - Ogawa M AD - Alexion, AstraZeneca Rare Disease, Boston, MA, USA. FAU - Ozol-Godfrey, Ayca AU - Ozol-Godfrey A AD - Alexion, AstraZeneca Rare Disease, Boston, MA, USA. FAU - Sierra, J Rafael AU - Sierra JR AD - Alexion, AstraZeneca Rare Disease, Boston, MA, USA. FAU - Szer, Jeff AU - Szer J AD - Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia. LA - eng SI - ClinicalTrials.gov/NCT03748823 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial DEP - 20221022 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - A3ULP0F556 (eculizumab) RN - 0 (Hemoglobins) RN - C3VX249T6L (ravulizumab) RN - 0 (Antibodies, Monoclonal, Humanized) MH - Adult MH - Humans MH - Follow-Up Studies MH - Hemoglobins MH - *Hemoglobinuria, Paroxysmal/drug therapy MH - Hemolysis MH - *Antibodies, Monoclonal, Humanized/therapeutic use PMC - PMC9589670 OAB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by the destruction of red blood cells (hemolysis) within blood vessels. In addition to hemolysis, patients with PNH are susceptible to life-threatening blood clots (thromboses). Eculizumab and ravulizumab are types of treatments for PNH, called C5 inhibitors. In the blood, these treatments bind to C5 protein and prevent the destruction of red blood cells, reducing the symptoms and complications of PNH. Both treatments are approved for use via intravenous (through the vein) administration. Ravulizumab is also approved in the USA for use via subcutaneous (under the skin) administration. This study compared subcutaneous ravulizumab with intravenous ravulizumab in patients with PNH who had previously been treated with eculizumab. During the initial treatment period of 71 days, 90 patients received subcutaneous ravulizumab and 46 received intravenous ravulizumab. Following this period, all patients received subcutaneous ravulizumab. At day 71, the amount of ravulizumab in the blood of patients taking subcutaneous ravulizumab was no less than in patients taking intravenous ravulizumab and was maintained over 1 year of treatment. Efficacy measures (how well it works) remained stable in patients taking subcutaneous ravulizumab for 1 year and side effects were comparable with those of intravenous ravulizumab. Patients reported more satisfaction with subcutaneous ravulizumab than intravenous eculizumab, as assessed by the Treatment Administration Satisfaction Questionnaire. This study showed that patients with PNH can switch from intravenous eculizumab or ravulizumab to subcutaneous ravulizumab without loss of efficacy. Subcutaneous ravulizumab provides an additional treatment choice for patients with PNH. OABL- eng OTO - NOTNLM OT - Non-inferiority OT - Paroxysmal nocturnal hemoglobinuria OT - Quality of life OT - Ravulizumab OT - Subcutaneous EDAT- 2022/10/23 06:00 MHDA- 2023/01/25 06:00 PMCR- 2022/10/22 CRDT- 2022/10/22 11:18 PHST- 2022/08/08 00:00 [received] PHST- 2022/09/26 00:00 [accepted] PHST- 2022/10/23 06:00 [pubmed] PHST- 2023/01/25 06:00 [medline] PHST- 2022/10/22 11:18 [entrez] PHST- 2022/10/22 00:00 [pmc-release] AID - 10.1007/s12325-022-02339-3 [pii] AID - 2339 [pii] AID - 10.1007/s12325-022-02339-3 [doi] PST - ppublish SO - Adv Ther. 2023 Jan;40(1):211-232. doi: 10.1007/s12325-022-02339-3. Epub 2022 Oct 22.