Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic condition that is usually acquired through somatic mutations and is characterized by the premature breakdown of erythrocytes in the blood (hemolysis). Elevated levels of free hemoglobin circulate through the blood, and eventually, the free hemoglobin is excreted in the urine, which appears darkened in the morning after accumulating in the bladder during the night.1

Clinical Trial Overview

According to the ClinicalTrials.gov registry, 117 clinical trials studying PNH have been recorded.2 To date, 

  • 65 trials have been completed;
  • 16 trials are currently active but not recruiting;
  • 21 studies are recruiting or enrolling by invitation; and
  • 2 studies are not yet recruiting.

The remaining studies have been suspended, terminated, or withdrawn or are of unknown status.2

Most completed studies examined the safety and efficacy of several different treatments proposed or developed for PNH, such as hematopoietic stem cell transplant and drugs including Soliris® (eculizumab), Ultomiris® (ravulizumab), Empaveli® (pegcetacoplan), zilucoplan, and others.2

Read more about PNH therapies

PIONEER Study

The PIONEER study is currently recruiting and aims to evaluate the safety and efficacy of Empaveli for the treatment of PNH-induced hemolytic anemia in adolescents between 12 and 17 years of age. The duration of the study may vary but will be 6 months at minimum.3 

PIONEER is an open-label clinical trial in which a 4-week screening period will be followed by a 16-week treatment period and a 2-month follow-up period or a long-term extension. Empaveli is administered via subcutaneous infusions twice weekly. The estimated study completion date is October 2024.4

Read more about Empaveli

COMMODORE 1 Study

COMMODORE1, which is currently recruiting, is an open-label, actively controlled, multicenter clinical trial that aims to determine if crovalimab is non-inferior to Soliris in patients with PNH who are currently being treated with complement inhibitors. The target enrollment is approximately 250 study participants, and the anticipated study completion date is July 24, 2030.5 

Crovalimab is an inhibitor of complement factor C5. It prevents C5 convertase from cleaving C5 into fragments that activate the complement cascade and increase erythrocyte hemolysis.6 

Participants in the treatment group will receive an intravenous dose of crovalimab on day 1, followed by weekly subcutaneous doses for 4 weeks. Maintenance dosing will start at week 5 and be administered monthly until study conclusion at 24 weeks. Participants in the Soliris group will receive a maintenance dose of the drug on day 1 and then every 2 weeks until study conclusion at 24 weeks. They will have the option to switch to crovalimab at the end of the study.5  

Read more about Soliris

COMMODORE 2 Study

COMMODORE 2 is currently recruiting patients and is similar to COMMODORE 1 in that it aims to compare crovalimab with Soliris in adult and adolescent patients who have PNH. The difference is that individuals eligible to participate in COMMODORE 1 are currently receiving treatment with complement inhibitors, whereas individuals eligible to participate in COMMODORE 2 have never received treatment with complement inhibitors. Target enrollment is approximately 200 participants, and the anticipated study completion date is June 30, 2028.7

Participants in the treatment group will receive an intravenous dose of crovalimab on day 1, followed by weekly subcutaneous doses for 4 weeks. Maintenance dosing will start at week 5 and be administered monthly until study conclusion at 24 weeks. Participants in the Soliris group will receive intravenous doses of the drug weekly for 4 weeks, followed by intravenous doses starting at week 5 that will be repeated every 2 weeks until study conclusion at 24 weeks.8

Read more about PNH experimental therapies

ACCESS 2 Study

ACCESS 2 is an open-label randomized controlled trial that is currently recruiting patients with PNH who are undergoing treatment with either Soliris or Ultomiris. The trial aims to evaluate the efficacy and safety of combination treatment with pozelimab and cemdisiran. The target enrollment is 140 participants, and the anticipated study completion date is September 18, 2026.9

Pozelimab is a human monoclonal antibody that inhibits complement factor C5 and prevents intravascular hemolysis in PNH.10 Cemdisiran is an investigational RNA interference (RNAi) therapeutic that suppresses the production of complement factor C5 in the liver. The drug is administered subcutaneously.11

Read more about Ultomiris

References

  1. Paroxysmal nocturnal hemoglobinuria. Medline Plus. Accessed November 18, 2022.
  2. Search for paroxysmal nocturnal hemoglobinuria. ClinicalTrials.gov. Accessed November 18, 2022.
  3. About the PIONEER study. Apellis Pharmaceuticals; 2022. Accessed November 18, 2022.
  4. A study of pegcetacoplan in pediatric patients with paroxysmal nocturnal hemoglobinuria (PNH). ClinicalTrials.gov. February 4, 2021. Updated July 20, 2022. Accessed November 18, 2022.
  5. A study evaluating the efficacy and safety of crovalimab versus eculizumab in participants with paroxysmal nocturnal hemoglobinuria (PNH) currently treated with complement inhibitors (COMMODORE 1). ClinicalTrials.gov. September 30, 2020. Updated September 26, 2022. Accessed November 18, 2022.
  6. Röth A, Nishimura J ichi, Nagy Z, et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020;135(12):912-920. doi:10.1182/blood.2019003399
  7. (COMMODORE 2) A phase III study evaluating the efficacy and safety of crovalimab versus eculizumab in adult and adolescent participants with paroxysmal nocturnal hemoglobinuria (PNH) not previously treated with complement inhibitors. Global PNH Patient Registry. AA MDS International Foundation. Accessed November 18, 2022.
  8. A phase III study evaluating the efficacy and safety of crovalimab versus eculizumab in participants with paroxysmal nocturnal hemoglobinuria (PNH) not previously treated with complement inhibitors (COMMODORE 2). ClinicalTrials.gov. October 8, 2020. Updated November 14, 2022. Accessed November 18, 2022.
  9. Efficacy and safety of the combination of pozelimab and cemdisiran versus continued eculizumab or ravulizumab treatment in adult patients with paroxysmal nocturnal hemoglobinuria (ACCESS 2). ClinicalTrials.gov. November 23, 2021. Updated February 14, 2022. Accessed November 18, 2022.
  10. Jang JH, Weyne J, Chaudhari U, et al. Pozelimab, a human monoclonal antibody against complement factor C5, provided inhibition of intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2021;138(Suppl 1):1128. doi:10.1182/blood-2021-146178
  11. Devalaraja-Narashimha K, Huang C, Cao M, et al. Pharmacokinetics and pharmacodynamics of pozelimab alone or in combination with cemdisiran in non-human primates. PLoS One. 2022;17(6):e0269749. doi:10.1371/journal.pone.0269749

Reviewed by Hasan Avcu, MD, on 11/23/2022.

READ MORE ON PNH