Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis
Abstract Background Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inh...
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | BMC Nephrology |
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| Online Access: | https://doi.org/10.1186/s12882-020-02190-0 |
| _version_ | 1818675259520319488 |
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| author | Anja Gäckler Ulf Schönermarck Vladimir Dobronravov Gaetano La Manna Andrew Denker Peng Liu Maria Vinogradova Sung-Soo Yoon Manuel Praga |
| author_facet | Anja Gäckler Ulf Schönermarck Vladimir Dobronravov Gaetano La Manna Andrew Denker Peng Liu Maria Vinogradova Sung-Soo Yoon Manuel Praga |
| author_sort | Anja Gäckler |
| collection | DOAJ |
| description | Abstract Background Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum. Methods This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [≥150 × 109/L], lactate dehydrogenase normalization [≤246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status. Results Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1–45.2] years) were diagnosed with aHUS and received ≥1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred. Conclusions Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment. Trial registration Clinical trial identifier: NCT02949128 . |
| first_indexed | 2024-12-17T08:24:44Z |
| format | Article |
| id | doaj.art-9339e685f80547318bdb36265bb477ae |
| institution | Directory Open Access Journal |
| issn | 1471-2369 |
| language | English |
| last_indexed | 2024-12-17T08:24:44Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Nephrology |
| spelling | doaj.art-9339e685f80547318bdb36265bb477ae2022-12-21T21:56:49ZengBMCBMC Nephrology1471-23692021-01-012211910.1186/s12882-020-02190-0Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysisAnja Gäckler0Ulf Schönermarck1Vladimir Dobronravov2Gaetano La Manna3Andrew Denker4Peng Liu5Maria Vinogradova6Sung-Soo Yoon7Manuel Praga8Department of Nephrology, University Hospital Essen, University Duisburg-EssenMedizinische Klinik IV, LMU Klinikum, LMUPavlov University, Research Institute of NephrologyDepartment of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, St. Orsola Hospital, University of BolognaAlexion Pharmaceuticals, Inc.Alexion Pharmaceuticals, Inc.National Medical Research Centre for Obstetrics and GynecologySeoul National University HospitalInstituto de Investigación Hospital Universitario 12 de Octubre i+12Abstract Background Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum. Methods This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [≥150 × 109/L], lactate dehydrogenase normalization [≤246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status. Results Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1–45.2] years) were diagnosed with aHUS and received ≥1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred. Conclusions Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment. Trial registration Clinical trial identifier: NCT02949128 .https://doi.org/10.1186/s12882-020-02190-0RavulizumabThrombotic microangiopathyPregnancy microangiopathiesAtypical hemolytic uremic syndrome |
| spellingShingle | Anja Gäckler Ulf Schönermarck Vladimir Dobronravov Gaetano La Manna Andrew Denker Peng Liu Maria Vinogradova Sung-Soo Yoon Manuel Praga Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis BMC Nephrology Ravulizumab Thrombotic microangiopathy Pregnancy microangiopathies Atypical hemolytic uremic syndrome |
| title | Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis |
| title_full | Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis |
| title_fullStr | Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis |
| title_full_unstemmed | Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis |
| title_short | Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis |
| title_sort | efficacy and safety of the long acting c5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy a subgroup analysis |
| topic | Ravulizumab Thrombotic microangiopathy Pregnancy microangiopathies Atypical hemolytic uremic syndrome |
| url | https://doi.org/10.1186/s12882-020-02190-0 |
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