FDA approves ravulizumab for PNH


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Ravulizumab (Ultomiris)

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 previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.

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.

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