STOCKHOLM, Sweden — A new drug under development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab (ALXN1210, Alexion Pharmaceuticals), has shown noninferiority compared with eculizumab (Soliris, Alexion Pharmaceuticals), currently the only therapy approved for the syndrome. But it achieved similar outcomes while being administered by intravenous (IV) infusion only once every 8 weeks, while eculizumab is given once every 2 weeks.
PNH is a rare, acquired, potentially life-threatening clonal hematopoietic stem cell disease, presenting with hemolytic anemia, an increased risk for thrombosis, and impaired bone marrow function.
"PNH patients with high disease activity require long-term treatment of eculizumab once treatment starts," first author Jong Wook Lee, MD, PhD, from Seoul St. Mary's Hospital College of Medicine, The Catholic University of Korea, Seoul, told Medscape Medical News.
"Considering the treatment burden of eculizumab administered IV every 2 weeks with a hospital visit or infusion center, ravulizumab every 8 weeks may be more convenient," Lee said.
Both drugs are C5 inhibitors, but ravulizumab has a half-life that is three to four times longer than that of eculizumab.
Although eculizumab reduces the need for blood transfusions in PNH, some patients may experience a loss of C5 inhibition during the treatment, potentially resulting in breakthrough hemolysis and PNH symptoms. Furthermore, the IV treatment is necessary every 2 weeks, Lee said.
Results of Head-to-Head Trial
The new results come from an open-label, multicenter trial, presented here at the European Hematology Association (EHA) 2018 Congress. Patients with PNH who had not previously been treated with complement inhibitors were randomly assigned to treatment with ravulizumab (n = 125) or eculizumab (n = 121) for 26 weeks.
Mean patient age was 44.8 years in the ravulizumab group and 46.2 years in the eculizumab group, and the mean number of years from PNH diagnosis was about 6.6 in both groups. All patients demonstrated at least one PNH-related symptom and lactate dehydrogenase (LDH) levels of 1.5 times the upper limit of normal at screening.
The IV ravulizumab regimen consisted of a loading dose, through day 15, of 2400 mg to 3600 mg, depending on body weight, followed by a maintenance dose every 8 weeks thereafter. For IV eculizumab, patients received the approved dosing regimen through day 183.
Nearly all patients completed the treatment, with the exception of two in the eculizumab group.
The study achieved its two primary endpoints of ravulizumab demonstrating noninferiority to eculizumab: the proportion of patients avoiding transfusion (73.6% vs 66.1%; difference, 6.8% [95% confidence interval (CI), –4.7% to 18.1%]) and normalization of LDH levels (53.6% vs 49.4%; odds ratio, 1.19 [95% CI, 0.80 - 1.77]).
Ravulizumab also had favorable changes in terms of the study's four key secondary endpoints: percentage change in least-square means of LDH levels (reduction from baseline of 76.8% with ravulizumab vs 76.0% with eculizumab); the change in fatigue, as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score (7.1- vs 6.4-point improvement from baseline, respectively); and percentages of patients with breakthrough hemolysis (4.0% vs 10.7%) and stabilized hemoglobin (68.0% vs 64.5%).
"The proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab group, which had 13 patients with 15 events, compared with the ravulizumab group, involving five patients and five events," Lee said.
"Furthermore, ravulizumab brought a numerically greater proportion of patients to normalized LDH, and in a more rapid manner," he added, noting that the median time to first LDH normalization was 24 (range, 22 to 29) days in ravulizumab recipients compared with 29 (range, 24 to 43) days in the eculizumab group.
Lee noted that among the 15 breakthrough hemolysis events in the eculizumab group, 7 resulted from suboptimal drug exposure or inadequate terminal complement inhibition, whereas no similar pharmacokinetic/pharmacodynamic effects occurred in the ravulizumab group.
"These differences are likely due to the immediate, complete, and sustained inhibition of C5 achieved by ravulizumab," he explained.
"Therefore, optimization of weight-based dosing with ravulizumab in the current study demonstrated clinical meaningful results, with extended [treatment] intervals," Lee said.
Similar Adverse Effects
There were no significant differences between the groups in terms of adverse events. The most common treatment-emergent adverse events were headache, occurring in about a third of patients in both groups (36.0% of the ravulizumab and 33.1% of the eculizumab group).
The groups also had similar rates of serious adverse events (8.8% and 7.4%, respectively).
Two patients in the ravulizumab group and one in the eculizumab group had major adverse vascular events, and no meningococcal infections were reported.
Lee noted that separate phase 3 studies of ravulizumab vs eculizumab in patients with PNH who were receiving prior eculizumab are ongoing, and those 26-week treatment results are expected to be presented at the American Society of Hematology meeting in December 2018.
In the meantime, the current study adds to evidence supporting treatment benefits, Lee said.
"The notable finding of this very well-designed study is the consistency of results across the six endpoints, each of which measures a different aspect of PNH," he said.
All Eyes on How Much Ravulizumab Will Cost
Importantly, eculizumab, an orphan drug that is also used in the treatment of atypical hemolytic uremic syndrome, has been the subject of controversy over its price. The cost reportedly ranges from about $400,000 to as much as $700,000 per year per patient, earning the drug a description in the press as one of "the world's most expensive drugs."
The marketing of the drug has also controversial, as detailed recently in a Bloomberg Businessweek article, "When the Patient Is a Gold Mine: The Trouble With Rare-Disease Drugs."
Lee told Medscape Medical News he had no information on the price Alexion expects to charge for ravulizumab, but Pieter Sonneveld, MD, EHA president, noted the cost will indeed be of interest.
"Since this drug has to be used lifelong, the pricing will be an important issue," said Sonneveld, who is professor of hematology and head of the Department of Hematology at the Erasmus MC Cancer Institute at the Erasmus University of Rotterdam, the Netherlands.
He agreed, however, that the findings of the head-to-head trial support potentially meaningful advantages for the new drug for patients with PHN.
"The major advantage of ravulizumab is its longer half-life resulting in more continuous C5 inhibition," Sonneveld said.
"It can be administered every 8 weeks, which results in sustained inhibition and hopefully fewer periods of hemolysis," he continued.
"For the PNH community it is important that several treatment options have now become available to treat their disease," he added.
The study was funded by Alexion Pharmaceuticals. Lee disclosed the receipt of honoraria, travel support, and research support from Alexion Pharmaceuticals. Sonneveld has disclosed no relevant financial relationships.
European Hematology Association (EHA) 2018 Congress. Abstract LB2603. Presented June 17, 2018.
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Cite this: New Drug for PHN Taken Only Once Every 8 Weeks - Medscape - Jul 02, 2018.