FDA Approves Ultomiris for Rare Blood Disorder

The FDA has approved Ultomiris (ravulizumab-cwvz) as an injection treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder that leads to hemolysis.

“We are proud to bring Ultomiris to patients suffering from this devastating disease less than a year after reporting our positive phase 3 data,” said John Orloff, M.D., executive vice president and head of research and development at Alexion, in a press release. “Immediate and complete C5 inhibition with Ultomiris, sustained for eight weeks, can provide meaningful benefits for patients and their families. Based on the totality of our compelling data from the largest phase 3 program ever conducted in PNH, we believe Ultomiris has the potential to become the new standard of care for patients with PNH.”

PNH is a rare acquired disorder that leads to hemolysis. Patients with PNH have episodes where red blood cells are prematurely destroyed, which may be triggered by stresses on the body. During these occurrences, severe anemia, profound fatigue, shortness of breath, intermittent episodes of dark colored urine, kidney disease or recurrent pain may occur. The disease is most often diagnosed in young adulthood, though it can occur at any age. Ultomiris, a long-acting C5 complement inhibitor, is designed to prevent hemolysis from occurring in patients.

The approval of Ultomiris is based on two phase 3 studies that demonstrated the noninferiority of Ultomiris to standard Soliris (eculizumab) in both treatment-naïve patients and those who received prior therapy with eculizumab.

In the first trial, the open-label phase 3 301 Study (NCT02946463), researchers evaluated the noninferiority of Ultomiris to Soliris in complement inhibitor—naïve adult patients with PNH with a lactate dehydrogenase (LDH) 1.5 times or more the upper limit of normal and at least 1 PNH symptom. A total 246 patients were randomized 1 to 1 to receive Ultomiris or Soliris for 183 days. The co-primary endpoints were the proportion of patients remaining transfusion-free and LDH normalization; secondary endpoints included percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5.

Results showed that Ultomiris given every eight weeks was noninferior to standard therapy in both the co-primary and all secondary endpoints, including transfusion avoidance (73.6 percent vs 66.1), LDH normalization (53.6 percent vs 49.4 percent; odds ratio 1.19), percent reduction in LDH (-76.8 percent vs -76.0), change in FACIT-Fatigue score (7.07 vs 6.40; difference), breakthrough hemolysis (4.0 percent vs 10.7 percent), and stabilized hemoglobin (68.0 percent vs 64.5).

In the second trial, the multicenter, open-label, phase 3 302 Study (NCT03056040), investigators evaluated treatment with Ultomiris in patients with PNH who had been previously treated with eculizumab and were clinically stable. A total 195 patients with PNH who previously received 900 mg of eculizumab every two weeks for six or more months were randomized 1 to 1 to switch treatment to Ultomiris (97 patients) or continue Soliris (98 patients). The primary endpoint was percentage change in LDH from baseline to day 183; key secondary endpoints included proportion of patients with breakthrough hemolysis, change in FACIT—Fatigue score, transfusion avoidance, and stabilized hemoglobin.

Results showed that in 191 patients who completed 183 days of treatment, Ultomiris given every eight weeks was noninferior to eculizumab, including percentage change in LDH (difference, 9.21 percent), breakthrough hemolysis (difference, 5.1 percent), change in FACIT-Fatigue score (difference, 1.47), transfusion avoidance (difference of 5.5 percent), and stabilized hemoglobin (difference, 1.4). The most frequently reported adverse event (AE) was headache in 26.8 percent of patients on Ultomiris compared with 17.3 percent of those on Soliris. No meningococcal infections or discontinuations due to AEs occurred.

Ultomiris does have a Boxed Warning regarding the risk of life-threatening meningococcal infections and sepsis. The FDA noted that patients should be immunized with meningococcal vaccines at least two weeks prior to administering the first dose of Ultomiris, unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection. Moreover, the agent is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.

“The approval of Ultomiris will change the way that patients with PNH are treated,” said Richard Pazdur, M.D., 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, in a press release. “Prior to this approval, the only approved therapy for PNH required treatment every two weeks, which can be burdensome for patients and their families. Ultomiris uses a novel formulation so patients only need treatment every eight weeks, without compromising efficacy.”

Regulatory agencies in the European Union and Japan have accepted and are reviewing applications for the approval of Ultomiris as a treatment for adults with PNH.

This article originally appeared on OncLive as "FDA Approves Ravulizumab for Paroxysmal Nocturnal Hemoglobinuria."