Normalization of Hemoglobin, Lactate Dehydrogenase, and Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease characterized by chronic complement-mediated hemolysis, thrombosis, bone marrow failure, and fatigue that impairs patients’ quality of life (QoL) [1, 2]. It is caused by acquired somatic mutations in the PIG-A gene in hematopoietic stem cells that prevents the complement inhibitors CD55 and CD59 from being expressed on red blood cells (RBCs) [2‐4]. RBCs derived from PNH hematopoietic stem cells are highly susceptible to complement-mediated lysis [2].

Clinical manifestations of PNH include anemia, abdominal pain, erectile dysfunction, and dysphagia, secondary to intravascular hemolysis (for which elevated lactate dehydrogenase [LDH] is a biomarker) [2, 5]. Other disease manifestations include thrombotic events, renal insufficiency, and bone marrow failure, as well as debilitating symptoms, such as fatigue or dyspnea, that impair QoL [2, 5].

Terminal complement activation and subsequent intravascular hemolysis in PNH are inhibited by complement component 5 (C5) inhibitors (e.g., eculizumab and ravulizumab) [2, 6‐8]. However, a substantial proportion of patients experience complement component 3 (C3)-mediated extravascular hemolysis during C5 inhibitor treatment [2, 9]. Up to 88% of patients receiving C5 inhibitors continue to have some degree of anemia due to residual intravascular hemolysis and emerging extravascular hemolysis, and up to 52% have required one or more RBC infusions within a 12-month period [2, 10]. In countries where complement inhibitors are not available, only supportive care (e.g., blood transfusions, prophylactic anticoagulants, corticosteroids, supplements) that manages PNH symptoms is available [11].

Pegcetacoplan is the first C3-targeting therapy for PNH and provides comprehensive hemolysis control [12, 13]. Pegcetacoplan studies in PNH have demonstrated rapidly improved clinical and fatigue parameters and a favorable safety profile [14‐17]. Previously reported results have not provided a comprehensive picture of the proportion of patients with PNH whose hematologic and quality-of-life outcomes improve to normal with pegcetacoplan treatment.

In the current analysis, we determined normalization rates for hemoglobin, LDH, and fatigue in patients with PNH treated with pegcetacoplan in two phase III trials: PEGASUS (pegcetacoplan vs. eculizumab in adults with hemoglobin < 10.5 g/dL despite ≥ 3 months of eculizumab therapy) and PRINCE (pegcetacoplan vs. supportive care only in complement inhibitor–naive patients) [14, 16, 17].

Patients enrolled in the PEGASUS trial [14] (NCT03500549) had PNH and anemia (hemoglobin < 10.5 g/dL) despite ≥ 3 months of eculizumab treatment. Patients enrolled in the PRINCE trial [16] (NCT04085601) were naive to complement inhibitor therapy (i.e., had not received treatment with any complement inhibitor [e.g., eculizumab, ravulizumab] within 3 months prior to screening), had hemoglobin concentrations below the lower limits of normal (females: < 12.0 g/dL; males: < 13.6 g/dL) and LDH concentrations ≥ 1.5 times the upper limit of normal (≥ 339 U/L), and received supportive care only (blood transfusions, corticosteroids, anticoagulants, and supplements [iron, folate, vitamin B₁₂]) in countries where complement inhibitors were not approved or widely available. Patients receiving supportive care in the PRINCE study could switch to pegcetacoplan treatment if their hemoglobin concentration decreased ≥ 2 g/dL below their baseline concentration or if they had a qualifying thromboembolic event secondary to PNH. In both PEGASUS and PRINCE, specific objective criteria for transfusions (hemoglobin < 7 g/dL regardless of whether symptoms are present, or < 9 g/dL with symptoms) were applied regardless of treatment assignment.

Normalization of hematologic and fatigue endpoints were assessed in PEGASUS at Week 16 (randomized controlled period; pegcetacoplan and eculizumab groups), and Week 48 (open-label period; pegcetacoplan-to-pegcetacoplan and eculizumab-to-pegcetacoplan groups) and in PRINCE at Week 26 (pegcetacoplan and supportive care [control] groups). Normalization for each endpoint was defined as follows:

Patients who received a transfusion (hemoglobin/LDH endpoints only), withdrew from the study, were lost to follow-up, or switched from control (supportive care only) to pegcetacoplan were considered not normalized. No additional statistical analysis was performed on the results from the PEGASUS and PRINCE trials.

Investigators reported treatment-emergent adverse events (TEAEs) by the Medical Dictionary for Regulatory Activities preferred terms through the end of the open-label period of PEGASUS and the end of PRINCE. The TEAEs of injection site reactions, infections, hemolytic disorders, thrombosis, and hypersensitivity were of special interest because of their relevance to PNH and potential relatedness to pegcetacoplan’s mechanism of action or route of administration. Event seriousness, severity, and relatedness to pegcetacoplan were determined by investigators. An adverse event (AE) was considered serious if the investigator viewed it as resulting in death, a life-threatening AE, inpatient hospitalization or prolongation of ongoing hospitalization, a persistent or significant incapacity or a substantial disruption of normal life functions, or a congenital anomaly or birth defect. Events that did not meet these criteria could have been considered serious if they jeopardized the patient’s health and required medical or surgical interventions to prevent one of the outcomes that defined a serious AE. The severity of an AE was defined as mild (i.e., resulted in mild or transient discomfort that did not limit or interfere with activities; did not require treatment), moderate (i.e., resulted in sufficient discomfort to limit or interfere with activities; may have required treatment), or severe (i.e., resulted in significant symptoms that prevented normal activities; may have required hospitalization or invasive intervention).

Original study protocols were designed and monitored in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki, and approved by an Institutional Review Board or independent Ethics Committee at each center [14, 16, 17]. Patients provided written informed consent before initiation of study-related procedures.

In this analysis of two phase III trials, PEGASUS and PRINCE, pegcetacoplan treatment rapidly resulted in sustained normalization of hemoglobin concentrations (in the absence of transfusions) and fatigue scores in a substantial percentage of patients with PNH compared with eculizumab or supportive care. Rates of LDH normalization (in the absence of transfusion), indicative of reduced intravascular hemolysis, were higher with pegcetacoplan versus eculizumab or supportive care. These results corroborate findings of rapidly improved clinical and fatigue parameters in pegcetacoplan studies in PNH [14‐17]. Across treatment groups, the median times to normalization among patients receiving pegcetacoplan were the shortest for LDH (1 day–2.5 weeks), followed by FACIT-Fatigue (2.3–4.1 weeks), and hemoglobin (4.1–6.1 weeks). PEGASUS patients normalized faster than PRINCE patients, and within PEGASUS, patients switching from eculizumab to pegcetacoplan normalized as fast (or slightly faster) as those who had been initially randomized to pegcetacoplan.

Studies of eculizumab and ravulizumab in PNH have demonstrated improvement in hemoglobin concentrations, although hemoglobin normalization occurs in only about 20–30% of patients treated with C5 inhibitors [19, 20]. Additionally, a recent survey-based study found high rates of persistent anemia, fatigue, and poor QoL among patients treated with C5 inhibitors [10]. The results of the current analyses demonstrate that pegcetacoplan fills unmet needs in the treatment of PNH by reducing rates of anemia and fatigue, and achieving better control of hemolysis compared with C5 inhibitors. In PEGASUS, hemoglobin, FACIT-Fatigue, and LDH normalization rates were markedly higher with pegcetacoplan versus eculizumab in patients who had anemia despite eculizumab treatment. This higher rate of LDH normalization with pegcetacoplan versus eculizumab (70.7% vs. 15.4%) may indicate that eculizumab was not sufficiently blocking the terminal complement pathway in these patients, resulting in residual intravascular hemolysis that was subsequently normalized with pegcetacoplan. In the complement inhibitor-naive patients in PRINCE, hemoglobin, FACIT-Fatigue, and LDH normalization rates were substantially higher with pegcetacoplan than with supportive care alone.

It is worth noting that although the hemoglobin normalization rates were markedly improved with pegcetacoplan, some patients did not have normalization. This could be explained by the bone marrow disorders, such as aplastic anemia, that are often present in patients with PNH, which limit the capacity for red blood production [21]. Future research that identifies common characteristics of patients without hemoglobin normalization, and the rates of normalization for patients with suboptimal bone marrow function, could identify patients who are likely to be less responsive to pegcetacoplan and develop appropriate treatment goals for these patients.

We observed that the percentages of patients with hemoglobin, LDH, and FACIT-Fatigue normalization decreased somewhat from week 16 to week 48 in eculizumab-experienced patients who were randomized to pegcetacoplan. The decreased normalization at week 48 could be an artifact of the analysis, in which patients who discontinued, died, or were censored because of transfusions were retained in the denominator, even though they could not have had normalization; this could have decreased the reported percentage of patients with normalization. It is also possible that the decreased normalization rates reflect variations in hemolysis that occurred spontaneously or because of complement-amplifying conditions (CACs; e.g., vaccinations, infections) [22]. CACs can reduce disease control because complement inhibitor therapy does not completely suppress the complement system, leaving room for hemolysis in times of high complement pathway activation [23]. Because this activation cannot always be avoided, the reasonable approach to address such hemolysis is to prevent CACs when possible and initiate an effective strategy to treat hemolysis events when they occur. Recent publications have shown that breakthrough hemolysis events in patients receiving pegcetacoplan can be well managed with temporary dosage increases [22, 23].

Despite the possibility of increased risk of encapsulated bacterial infections with broad complement inhibition [24], no cases of meningococcal infection were noted in either trial, and a single case of sepsis (biliary) possibly related to pegcetacoplan was reported in the 32-week open-label period in PEGASUS. Safety results in these studies indicate that pegcetacoplan was generally well tolerated.

This study had several limitations. This analysis was not designed to identify the percentage of patients who had normalization of all three endpoints (i.e., hemoglobin, LDH, and FACIT-Fatigue). Another limitation is that the normalization analyses included all patients, regardless of their eligibility for normalization, which could have resulted in artificially low normalization rates. In addition, a longer study duration would have provided more information about response durability. Future studies to identify clinical markers that predict normalization with pegcetacoplan and to discern differences in safety by normalization status could provide useful guidance for treatment decisions.

These results demonstrate that pegcetacoplan is superior to both eculizumab and supportive care in achieving normalization of hemoglobin, LDH, and FACIT-Fatigue scores in patients with PNH and persistent anemia despite at least 3 months of treatment with eculizumab, and in C5 inhibitor–naive patients with PNH.