In patients with paroxysmal nocturnal hemoglobinuria (PNH), treatment with the C3 inhibitor pegcetacoplan has been associated with improvements in measures of fatigue, according to findings from a post hoc analysis of the randomized, controlled PEGASUS trial published in the European Journal of Haemotology.

Individuals with the rare, acquired hematologic condition PNH can experience complement-mediated hemolytic anemia, bone marrow failure, intravascular hemolysis, thrombosis, and renal insufficiency. The elevated level of disease activity observed in these patients often presents with such symptoms as anemia-associated fatigue/weakness, abdominal pain, and dyspnea, along with possible organ dysfunction and smooth muscle dysfunction.

These events can impact patients’ health-related quality of life, thus imposing a significant cost burden on healthcare systems. Fatigue, which is frequently the most common symptom reported among patients with PNH, can have a remarkably negative impact on a person’s health-related quality of life and work productivity.

Eculizumab was the first anti-C5 monoclonal antibody treatment developed for adults and children with PNH that was associated with sustained inhibition of complement-mediated intravascular hemolysis. Some individuals treated with C5 inhibitor therapy continue to experience intravascular hemolysis breakthrough hemolysis or C3-mediated extravascular hemolysis, remaining anemic and reporting increased fatigue. These individuals may experience thrombotic complications, along with increased morbidity.

Read more about PNH diagnosis

Recognizing that pegcetacoplan may have the ability to act proximally in the complement cascade, thus controlling intravascular and extravascular hemolysis, the investigators of the pivotal phase 3 PEGASUS trial sought to compare treatment with pegcetacoplan vs eculizumab in patients with PNH. In this post hoc analysis of PEGASUS, they compared improvements in patient-reported fatigue calculated with the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-fatigue) instrument item-level ratings for the 2 agents in individuals with the disorder.

Patients in PEGASUS were treated with a stable dose of eculizumab combined with 1080 mg of self-administered subcutaneous pegcetacoplan, twice weekly during a 4-week run-in period. This was followed by randomization, in a 1:1 ratio, to 16 weeks of pegcetacoplan monotherapy in 41 participants or eculizumab monotherapy in 39 participants. Seventy-seven patients completed the randomized, controlled phase and then entered the open-label phase (ie, weeks 17-48).

FACIT-fatigue contains 13 individual items, each of which is rated on a 5-level Likert scale. In the analysis, a 2-level change or more against the minimally clinically important difference of FACIT-fatigue total score (≥5 points) and clinically important response, hemoglobin of 1 g/dL of greater, and normalized absolute reticulocyte count (30-100 pg/cells) were all evaluated.

Results of the study showed that pegcetacoplan compared with eculizumab was associated with a significantly increased likelihood of week 16 clinically important response in 8 of 13 of the FACIT-fatigue items, as well as on a total score minimally clinically important difference (odds ratio, 11.19; 95% CI, 3.73-33.57), along with more rapid time to responses. Additionally, the item-level clinically important response threshold demonstrated clinical relevance on absolute reticulocyte count normalization and hemoglobin level.

The authors concluded, “The results of this [post hoc] analysis of the PEGASUS trial data indicate that, compared with eculizumab, treatment with pegcetacoplan was associated with clinically meaningful greater improvements [in] a majority of FACIT-fatigue items.”


Panse J, Wilson K, Fishman J, et al. Fatigue and health-related quality of life in paroxysmal nocturnal haemoglobinuria: a post-hoc analysis of the pegcetacoplan PEGASUS trial data. Eur J Haematol. Published online March 25, 2023. doi:10.1111/ejh.13969