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Mature black woman looking at microscope in laboratory

The biggest clinical concern in cases of paroxysmal nocturnal hemoglobinuria (PNH) is the twin manifestation of intravascular hemolysis and thrombosis—two conditions that drive morbidity and mortality. 

Pegcetacoplan, a drug that targets the proximal complement protein C3, has been shown to reduce the risk of intravascular hemolysis and thrombosis. This drug received approval for the treatment of patients with PNH from the US Food and Drug Administration in May 2021, becoming the third drug approved to treat this rare condition (after eculizumab and ravulizumab).

In a letter to the editor of Blood, Griffin and colleagues wrote about their study on the merits of the drug in alleviating some of the manifestations of PNH. In this letter, they highlighted the potentially life-threatening implications of breakthrough intravascular hemolysis: it is typically accompanied by a sudden drop in hemoglobin levels, a rise in lactate dehydrogenase, and an increase in PNH-related symptoms (fatigue, dyspnea, abdominal pain, and dysphagia, among others).

Eculizumab, which is prescribed to all patients with PNH unless contraindicated, can partially hold off such events. However, a risk of breakthrough intravascular hemolysis can accompany the end of an eculizumab dosing interval or during events that amplify the aberrant complement pathway in PNH, such as infection. 

Read more about PNH etiology 

Eculizumab binds the complement protein C5 in the complement cascade, which in effect inhibits terminal complement activation. However, Griffin et al noted that breakthrough intravascular hemolysis can be paradoxically more severe in patients on C5 inhibition due to the speed at which hemolysis occurs. In addition, roughly two-thirds of patients on eculizumab are anemic because of C3 red cell opsonization leading to extravascular hemolysis, which may require treatment with blood transfusions. Therefore, it is best practice for eculizumab’s users to be made aware of these risks so they will seek clinical treatment if symptoms arise. 

Examining the Merits of Pegcetacoplan in PNH 

In the same letter, Griffin and coauthors wrote that their center participated in a study in which the merits of pegcetacoplan were clinically assessed; for this study, they recruited 5 patients who experienced transfusion-dependent extravascular hemolysis while taking eculizumab. 

When the patients were put on pegcetacoplan, their mean red cell population rose from 42.25% to 96.25%. However, even with the use of pegcetacoplan, they experienced a total of 7 breakthrough events—2 were unprecipitated, whereas 5 were triggered by vaccination or infection (all cases of infections were treated). 

Three of the 6 events were treated with single eculizumab doses; 1 among them also required an increase in pegcetacoplan dosing frequency. The other 3 events occurred in the same individual: the first after 19 days of eculizumab cessation, which was treated with eculizumab reintroduction; the second episode was treated with an increase in both eculizumab and pegcetacoplan dosing. The third episode prompted another increase in eculizumab dosing and the prescription of daily subcutaneous pegcetacoplan for 3 days. 

This trial demonstrated 2 things: first, patients who were on pegcetacoplan were still at risk of experiencing breakthrough events; second, eculizumab may have a role in augmenting the effects of increased pegcetacoplan dosing in terminating these events. 

“Many questions remain regarding the diagnosis and management of PNH breakthrough events associated with complement inhibitors,” the authors of the letter wrote. “As proximal complement inhibitors become more widely available, the management of breakthrough events should become clearer, and the identification of patients who require combination treatment will hopefully become more evident.” 

Additional Evidence for Pegcetacoplan Use 

While Griffin and colleagues adopted a more qualified approach when evaluating the merits of pegcetacoplan use in patients with PNH, other researchers offer a more optimistic picture. 

In Therapeutic Advances in Hematology, RSM Wong from the Chinese University of Hong Kong presented a brief overview of the trials that have investigated whether pegcetacoplan can alleviate PNH pathology in the short and long term. For example, the PHARAOH study assessed the number and severity of treatment-emergent adverse events (TEAEs) with pegcetacoplan usage and evaluated whether its pharmacokinetic data fell within acceptable parameters. 

The researchers of the study recruited 9 patients, with 4 completing the trial for the full duration of 2 years. Overall, the research team reported 68 TEAEs that could possibly be associated with pegcetacoplan, 48 of them related to the drug injection site. These data were interpreted as proof of pegcetacoplan’s relative safety and tolerability. In addition, researchers concluded that it improved “hematological outcomes by achieving broad control of hemolysis through C3 inhibition.” 

Read more about PNH treatment 

However, both trials above were conducted in patients who were first treated with eculizumab; how would patients with PNH fare if they were complement inhibitor-naive? Two trials, called PADDOCK and PALOMINO, sought to answer this question, with the primary efficacy endpoints being changes in hemoglobin, haptoglobin, and lactate dehydrogenase levels. Both studies saw improvements in all 3 parameters on day 365 in eculizumab-naive patients after the initiation of pegcetacoplan. 

Commenting on the available studies on pegcetacoplan use in patients with PNH, Wong concluded, “Results from phase I–III clinical trials suggest that pegcetacoplan is efficacious and safe in a broad population of patients with PNH.” 

Further research is required to examine the strengths and weaknesses of pegcetacoplan from as many angles as possible. The real issue here is the relative lack of therapeutics for PNH, and that both eculizumab and pegcetacoplan work by targeting the complement system. As research advances and therapeutic choices improve, clinicians and their patients will be better able to tailor treatment according to disease course and presentation. 


Griffin M, Muus P, Munir T, et al. Experience of compassionate-use pegcetacoplan for paroxysmal nocturnal hemoglobinuriaBlood. 2023;141(1):116-120. Published online January 5, 2023. doi:10.1182/blood.2022017266

Wong RSM. Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuriaTher Adv Hematol. 2022;13:20406207221114673. Published online July 28, 2022. doi:10.1177/20406207221114673