Real-world data confirm benefits of ravulizumab for atypical hemolytic uremic syndrome
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Key takeaways:
- Registry data showed efficacy of ravulizumab was similar to that of eculizumab.
- No unexpected adverse events were reported for patients who switched from treatment with eculizumab to ravulizumab.
Adults and children with atypical hemolytic uremic syndrome who switched from eculizumab to ravulizumab had stable renal function and hematologic values with similar safety seen in clinical trials, according to data from a registry study.
“Atypical hemolytic uremic syndrome (aHUS) is a progressive rare disease that, if untreated, can result in severe organ damage and death. ... Eculizumab, a humanized monoclonal antibody that blocks terminal complement activation by inhibiting
cleavage of complement C5, was approved for the treatment of aHUS in 2011 and revolutionized the clinical management of aHUS,” Franz Schaefer, MD, PhD, professor of pediatrics and chief of pediatric nephrology at Heidelberg University Hospital in Germany, and colleagues wrote in background to the study published in KI Reports. “The efficacy and safety of [the next-generation terminal complement inhibitor] ravulizumab [Ultomiris, Alexion] in patients with aHUS have been demonstrated in clinical trials, in which ravulizumab was shown to provide immediate, complete and sustained complement C5 inhibition.”
To assess real-world efficacy and safety of ravulizumab among adult and pediatric patients, researchers analyzed data from the Global aHUS Registry, an ongoing registry sponsored by Alexion Pharmaceuticals begun in 2012 that includes data on patients in 23 countries.
“The registry has the largest real-world cohort of patients with aHUS and is open to all patients, regardless of treatment status, providing reasonable representation of the global aHUS patient population,” the researchers wrote.
To assess ravulizumab safety, researchers evaluated data on all registry patients who switched from eculizumab to ravulizumab therapy — 43 adults (73% women; median age at start of ravulizumab, 37 years; median eculizumab duration, 66 months; median ravulizumab duration, 23 months) and 17 children (78% girls; median age at start of ravulizumab, 8 years; median eculizumab duration, 62 months; median ravulizumab duration, 20 months).
No unexpected adverse events were reported during treatment with ravulizumab. Overall, 20 adverse events were reported among 13 patients. Two were deemed related to treatment: an infusion reaction that resolved within 24 hours and headache and fatigue that led the patient to discontinue the medication. Two other patients discontinued ravulizumab on the advice of their physicians. Three serious adverse events occurred: squamous cell carcinoma, atrial fibrillation and SARS-CoV-2 infection. The most common adverse event was infection, and there were no cases of meningococcal infection and no deaths.
To assess efficacy, the researchers focused on data from patients who were prescribed eculizumab and switched less than 1 month later to ravulizumab for at least 3 months beginning on or after Oct. 1, 2019 — 40 adults and nine children.
No patients proceeded to dialysis or kidney transplantation after switching to ravulizumab. Following local guidelines, one patient switched back to eculizumab for a planned kidney transplant, according to researchers. No new thrombotic microangiopathy symptoms developed after switching to ravulizumab, and relevant laboratory values remained stable.
“These data provide further evidence for the safety and effectiveness of ravulizumab treatment in patients with aHUS who switched from eculizumab and reinforce a positive risk-benefit profile of ravulizumab. Further studies in other aHUS subpopulations, including treatment-naive patients, would be beneficial to guide clinical practice,” the researchers wrote.
Perspective
Back to TopAtypical hemolytic uremic syndrome is a thrombotic microangiopathy caused by complement dysregulation. Uncontrolled terminal complement activation can result in severe organ damage and death. The current standard treatment for aHUS, which affects fewer than 625 patients in the U.S., is eculizumab, which blocks terminal complement activation and is effective for 90% of patients but is expensive and is associated with frequent meningococcal disease . Changing four amino acids in its complement binding and neonatal Fc regions led to the development of ravulizumab with a longer half-life and, in clinical trials, similar safety and efficacy.
Schaefer and colleagues aimed to evaluate the safety and efficacy of ravulizumab in real-world usage by analyzing data from a global aHUS registry that was initiated in April 2012 by 23 countries. Patients were included in the efficacy analysis after 3 months of ravulizumab. Patients were excluded if they had less than 1 month between eculizumab discontinuation and ravulizumab initiation or if they discontinued eculizumab, relapsed and then initiated treatment with ravulizumab.
Sixty patients were entered into the registry: 43 were adults; 17 were pediatric. All were included in the safety analysis; 49 were included in the efficacy analysis. Family history of aHUS was present in 18%. There were insufficient data on genetic analyses to draw conclusions. Among patients who switched to ravulizumab, there were no new dialysis or transplant events and no new thrombotic microangiopathy symptoms. Creatinine, hemoglobin, platelet and LDL levels were stable. Twenty adverse events were reported in 13 patients, including three serious adverse events, none of which were treatment related. There were no reports of meningococcal disease.
Ravuzliumab appears to have similar safety and efficacy profiles as eculizumab for treatment of aHUS with an advantageous administration protocol. The expense of these drugs and the risk of meningococcal disease warrant an ongoing search for better treatment options.
Reference:
Dunn S, et al. BMJ Open. 2022;doi:10.1136/bmjopen-2021-054536.
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