In patients with paroxysmal nocturnal hemoglobinuria (PNH), more frequent dosing of the C3 inhibitor pegcetacoplan has been shown to control breakthrough hemolysis (BTH), according to findings from a case study published in the journal eJHaem.

Historically, the rare, acquired, life-threatening complement-mediated hemolytic disorder PNH is well controlled with use of the terminal complement pathway inhibitor eculizumab. The agent has been shown to prevent thrombolytic events from developing, control intravascular hemolysis, and improve survival among patients with the disease. In many patients, the use of the longer-acting C5 inhibitor ravulizumab has further enhanced the treatment experience.

In a group of individuals with PNH, however, extravascular hemolysis persists despite these therapeutic interventions, leading to anemia and subsequent red blood cell transfusions. In fact, in certain patients, BTH can persist and thus remain an ongoing issue.

In the recent phase 3, controlled, open-label PEGASUS trial ( NCT03500549), treatment with pegcetacoplan was superior to eculizumab in patients with PNH and ongoing anemia. Pegcetacoplan improved hemoglobin levels, as well as clinical and hematologic outcomes, by providing broad hemolysis control, including that of intravascular hemolysis and extravascular hemolysis. 

Read more about experimental therapies for PNH

The current case report describes the normalization of hemoglobin levels associated with the resolution of extravascular hemolysis and the control of intravascular hemolysis with pegcetacoplan therapy over a 15-month period once the patient’s dosing was optimized. It is the first case to report on using additional doses of pegcetacoplan to manage BTH in a patient with PNH.

The patient was a retired 76-year-old businessman from Melbourne, Australia, who had been diagnosed with PNH in 1993, when he was 48 years of age. His chief complaints at presentation were episodic hemoglobinuria, iron deficiency anemia, and intermittent abdominal pain. In 2008, he underwent PNH clone assessment via flow cytometry and received red blood cell transfusions. At that time, treatment with eculizumab was initiated.

The patient’s initial eculizumab dosing in 2008 was 900 mg administered intravenously (IV) every 2 weeks. In 2012, the dosing was increased to 1200 mg every 2 weeks because of BTH symptoms, difficulty swallowing, and hemoglobinuria. In September 2020, his eculizumab dose was increased to 1200 mg IV every 12 days because of BTH symptoms once again.

Read more about testing for PNH

Although his intravascular hemolysis was reasonably controlled, his extravascular hemolysis continued, and he required transfusions on an approximately monthly basis between 2010 and 2020. In October 2020, treatment with the recently approved pegcetacoplan was initiated at a 1080-mg subcutaneous dose (SC) two times a week. Crossover with ongoing eculizumab continued for 1 month, and that agent was then discontinued.

Treatment with pegcetacoplan was associated with normalization of lactate dehydrogenase levels and rising hemoglobin levels. Because of several additional episodes of BTH, his pegcetacoplan dose was increased to 1080 mg SC daily for 3 consecutive days, which resolved his hemolysis. Following this, his pegcetacoplan dose was ultimately increased to 1080 mg SC 3 times weekly. This dose controlled both intravascular and extravascular hemolysis, and was associated with symptomatic improvement of his anemia.

“This case illustrates that dose adjustment may be required to prevent BTH and that options for treatment of BTH . . . include additional doses of pegcetacoplan or use of eculizumab,” the researchers concluded.


Davis AK, Bingham N, Szer J. Normalisation of haemoglobin and control of breakthrough haemolysis with increased frequency pegcetacoplan dosing in treated paroxysmal nocturnal haemoglobinuria. eJHaem. Published online May 10, 2023. doi:10.1002/jha2.714