The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.