The US Food and Drug Administration (FDA) has approved ravulizumab (Ultomiris, Alexion Pharmaceuticals) injection, the first and only long-acting C5 complement inhibitor for adults with paroxysmal nocturnal hemoglobinuria(PNH), a rare blood disease.

"The approval of Ultomiris will change the way that patients with PNH are treated," Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in a news release announcing approval. "Ultomiris uses a novel formulation so patients only need treatment every 8 weeks, without compromising efficacy," said Pazdur.

PNH Eculizumab

Until now, the only approved therapy for PNH eculizumab (Soliris, also from Alexion) required treatment every 2 weeks, "which can be burdensome for patients and their families," said Pazdur. 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.

Eculizumab and Ravulizumab

Both eculizumab and ravulizumab are C5 inhibitors that prevent hemolysis, but ravulizumab has a half-life that is three to four times longer than that of eculizumab. The efficacy of ravulizumab was studied in 246 patients with PNH who had not previously been treated with complement inhibitors. Patients were randomly assigned to treatment with ravulizumab every 8 weeks (n = 125) or eculizumab every 2 weeks (n = 121) for 26 weeks.

The study showed that ravulizumab was non-inferior to eculizumab, with a similar proportion of patients in each group avoiding transfusion and achieving a normalization of lactate dehydrogenase (LDH) levels. Ravulizumab was also examined in a second study of 195 patients with PNH who were clinically stable after treatment with eculizumab for at least the past 6 months.

These patients were randomly assigned to continue eculizumab or switch to ravulizumab. Again, ravulizumab demonstrated similar effects to eculizumab (non-inferior) based on several clinical measures, including hemolysis and avoiding transfusion, the FDA said. The safety profile of ravulizumab was similar to eculizumab. Common side effects seen in clinical trials include headache and upper respiratory infection.

Ravulizumab includes a boxed warning about the risk of life-threatening meningococcal infections and sepsis. Patients should be immunized with meningococcal vaccines at least 2 weeks prior to administering the first dose of ravulizumab, unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection.

Vaccination reduces, but does not eliminate, the risk of meningococcal infection, the FDA said, and patients should be monitored for early signs of meningococcal infections and evaluated immediately if infection is suspected. Ravulizumab is available only in conjunction with a Risk Evaluation and Mitigation Strategy (REMS) program and must be given with a patient medication guide that describes the drug's uses and risks. Ravulizumab had orphan drug designation and priority review. The FDA approved the drug nearly 2 months ahead of schedule.