Paroxysmal Nocturnal Hemoglobinuria (PNH)


Ultomiris® (ravulizumab) is a US Food and Drug Administration (FDA)-approved humanized monoclonal antibody against the complement protein C5 that was developed by Alexion Pharmaceuticals. It is used to treat children (at least 1 month of age and 5 kg body weight) and adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare fatal disease characterized by intravascular hemolytic anemia, thrombosis, smooth muscle dystonias, and, in rare cases, bone marrow failure.1

The FDA granted Orphan Drug designation to intravenous Ultomiris in 2017, followed by the acceptance of a biologics license application and the granting of a priority review in August 2018. Finally, in December 2018, Ultomiris was approved in the United States for the treatment of adult patients with PNH.2

Get full prescribing information for Ultomiris at MPR

Mechanism of Action

Ultomiris was designed based on the first-generation C5 inhibitor, Soliris® (eculizumab). However, Ultomiris is longer acting, with a mean half-life that is 4 times longer than that of Soliris. Because of this, it requires fewer infusions, ultimately reducing the treatment burden associated with Soliris through an improved dosing regimen.3

Ultomiris binds specifically to the complement protein C5 with high affinity to block its activation, inhibiting its cleavage into C5a (proinflammatory anaphylatoxin) and C5b (initiating subunit of the terminal complement complex). This prevents the formation of the terminal complement complex C5b-9, which ultimately prevents the lysis of red blood cells. Thus, Ultomiris provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals, thereby reducing the symptoms of the disease.1

Read more about PNH pathophysiology

Administration

Ultomiris is administered as an intravenous infusion in adults and pediatric patients or as a subcutaneous injection for maintenance in adults only. The recommended dose depends on the patient’s body weight. Patients receive an initial loading dose, followed by a maintenance dose 2 weeks later, which is administered intravenously every 8 weeks throughout life. In patients who switch from Soliris to Ultomiris, the loading dose should be administered 2 weeks after the last Soliris infusion. For pediatric patients, the maintenance dose is administered every 4 or 8 weeks (depending on body weight).1,4

Adverse Effects

The most common side effects of Ultomiris (affecting more than 10% of patients) are upper respiratory tract infection and headache. Local injection site reactions and diarrhea are among the most common side effects of Ultomiris when given subcutaneously. Ultomiris can cause serious infusion-related reactions, with symptoms such as lower back pain, faintness, arm or leg discomfort, chest pain, breathing problems, and swelling of face, tongue, or throat.4 

Other less common adverse reactions reported in both Soliris-experienced and complement inhibitor naive adult PNH patients treated with intravenous Ultomiris (affecting 5% or more patients) are diarrhea, nausea, abdominal pain, pyrexia, pain in extremities, arthralgia, and dizziness.4

Read more about PNH complications

Warnings and Precautions

Ultomiris affects the ability of the immune system to fight infections and increases the chances of acquiring serious infections, such as those caused by Streptococcus pneumoniae and Haemophilus influenzae type b, as well as life-threatening meningococcal infections caused by Neisseria meningitidis. Thus, patients with PNH must receive vaccinations to prevent these infections.4

Patients with unresolved N meningitidis infection and patients who are not currently vaccinated against N meningitidis are advised against treatment with Ultomiris. However, unvaccinated patients may be prescribed this medicine if the risk of delaying Ultomiris treatment outweighs the risk of developing a meningococcal infection.4

Read more about PNH prognosis

Safety and Efficacy in Trials

In two phase 3 studies conducted in adult patients with PNH, Ultomiris given every 8 weeks was found to be similar in safety and efficacy to Soliris given every 2 weeks in reducing the breakdown of red blood cells and avoiding the need for blood transfusions. In both studies, fewer patients experienced breakthrough hemolysis events when treated with Ultomiris than when receiving Soliris.6

In the first open-label, 26-week phase 3 study (NCT02946463),5 246 C5 inhibitor-naive patients who had not been previously treated with Soliris received either Ultomiris every 8 weeks or Soliris every 2 weeks. After 6 months of treatment, similar benefits were seen in both groups, with no need for blood transfusion in 73.6% of patients given Ultomiris and 66.1% of patients given Soliris. In addition, around half of the patients in each group (53.6% of patients given Ultomiris and 49.4% of patients given Soliris) had achieved normal blood levels of lactate dehydrogenase (LDH), a marker of hemolysis. Further, fewer patients experienced breakthrough hemolysis events with Ultomiris treatment than with Soliris therapy (4% vs 10.7%).6 An open-label extension study demonstrated that Ultomiris treatment was safe and effective over 52 weeks, with complete and sustained C5 inhibition and a reduced incidence of breakthrough hemolysis.7

In the second open-label, phase 3 study (NCT03056040)8 that enrolled 195 patients with PNH who did not have symptoms after at least 6 months of treatment with Soliris (900 mg every 2 weeks), patients either continued treatment with Soliris or switched to Ultomiris. Transfusion avoidance was achieved in 87.6% of patients receiving Ultomiris vs 82.7% of patients receiving Soliris. The mean percentage change in blood LDH levels after 6 months of treatment was -0.82% for Ultomiris-treated patients and 8.39% for Soliris-treated patients. In addition, none of the patients treated with Ultomiris had a flare-up of symptoms during this time, while 5 of those continuing Soliris did. Fewer patients experienced breakthrough hemolysis with Ultomiris than with Soliris (0% vs 5.1%).9

A third open-label, 26-week phase 3 study (NCT03406507)10 assessing the safety and efficacy of Ultomiris in pediatric patients showed comparable benefits with Ultomiris in 13 patients under the age of 18 years who were either complement inhibitor-naive or stable on treatment with Soliris. After 6 months of treatment, 60% of previously untreated patients and 50% of Soliris-treated patients had normal levels of LDH. In addition, 60% of previously untreated patients and 100% of previously treated patients did not need blood transfusions during treatment. The results showed that the efficacy of intravenous Ultomiris in pediatric patients was similar to that observed in adult patients.11

Read more about PNH clinical trials

References

  1. McKeage K. Ravulizumab: first global approval. Drugs. 2019;79(3):347-352. doi:10.1007/s40265-019-01068-2
  2. FDA approves ravulizumab-cwvz for paroxysmal nocturnal hemoglobinuria. US Food and Drug Administration (FDA). Accessed November 28, 2022.
  3. Brodsky RA, Peffault de Latour R, Rottinghaus ST, et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica. 2021;106(1):230-237. doi:10.3324/haematol.2019.236877
  4. Ultomiris. Prescribing information. Alexion Pharmaceuticals, Inc; 2022. Accessed November 28, 2022.
  5. ALXN1210 (ravulizumab) versus eculizumab in complement inhibitor treatment-naïve adult participants with paroxysmal nocturnal hemoglobinuria (PNH). ClinicalTrials.gov. October 27, 2016. Updated August 9, 2022. Accessed November 28, 2022.
  6. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019;133(6):530-539. doi:10.1182/blood-2018-09-876136
  7. Schrezenmeier H, Kulasekararaj A, Mitchell L, et al. One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study. Ther Adv Hematol. 2020;11:2040620720966137. doi:10.1177/2040620720966137
  8. ALXN1210 versus eculizumab in adult participants with paroxysmal nocturnal hemoglobinuria (PNH) currently treated with eculizumab. ClinicalTrials.gov. February 16, 2017. Updated July 21, 2022. Accessed November 28, 2022.
  9. Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540-549. doi:10.1182/blood-2018-09-876805
  10. A study of ravulizumab (ALXN1210) in children and adolescents with paroxysmal nocturnal hemoglobinuria. ClinicalTrials.gov. January 23, 2018. Updated October 7, 2022. Accessed November 28, 2022.
  11. Kulagin A, Chonat S, Maschan A, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria: interim analysis of a phase 3, open-label study. Poster presented at: European Hematology Association (EHA) 2021 Virtual Congress; June 9-17, 2021; Virtual.

Reviewed by Debjyoti Talukdar, MD, on 11/28/2022.