Digital Features for this Adis Drug Evaluation can be found at https://doi.org/10.6084/m9.figshare.21405492

FormalPara Pegcetacoplan: clinical considerations in PNH

First C3 inhibitor approved for adults with PNH

Improves clinical and haematological parameters of haemolysis in complement inhibitor-naïve patients and in patients previously treated with eculizumab

Improves QOL and fatigue symptoms to a clinically meaningful extent

Generally well tolerated

1 Introduction

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disorder that is characterized by complement-mediated haemolysis, fatigue and thrombotic events [1,2,3]. PNH is caused by acquired mutations in the phosphatidylinositol glycan anchor biosynthesis class A gene on haematopoietic stem cells (HSCs). This gene is required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, which link various cell-surface proteins to the cell membrane on HSCs [1,2,3].

Complement-mediated haemolysis, one of the primary clinical manifestations of PNH, is caused by the lack of GPI-anchored regulatory proteins CD55 and CD59 on the surface of red blood cells (RBC) [1, 2]. CD55 accelerates the decay of complement component 3 (C3) convertases, thereby inhibiting proximal complement cascade and preventing C3-mediated extravascular haemolysis [2, 3]. On the other hand, CD59 blocks the aggregation of C9 with other component molecules, such as C5b, C6, C7 and C8, to form membrane attack complex (MAC), thereby inhibiting terminal complement activation and preventing MAC-mediated intravascular haemolysis [2, 3].

The management of PNH was traditionally centred around supportive care (e.g. blood transfusion, thrombosis prevention) and allogeneic bone marrow transplantation [1]. However, the development of C5 inhibitors, such as eculizumab and ravulizumab, has substantially improved clinical outcomes in patients with PNH, producing a paradigm shift in the management of PNH [3, 4]. Eculizumab and ravulizumab have demonstrated long-term efficacy in the management of PNH by decreasing intravascular haemolysis (Fig 1), leading to improvements in anaemia, fatigue and quality of life (QOL), and reductions in blood transfusions and thrombotic events [2, 3]. However, many patients treated with C5 inhibitors continue to experience persistent anaemia and exhibit signs and symptoms of ongoing haemolysis (e.g. fatigue and the need for blood transfusions) because C5 inhibitors cannot decrease extravascular haemolysis, which is facilitated by C3b opsonization. Other causes of suboptimal responses to C5 inhibitors include polymorphisms in C5 and residual terminal intravascular haemolysis [2, 3]. Consequently, there is an unmet need to develop a complement inhibitor that targets both intravascular and extravascular haemolysis.

Fig 1
figure 1

Mechanism of action of complement inhibitors in paroxysmal nocturnal haemoglobinuria. Please note that the diagram depicts a portion of the complement cascade where complement inhibitors act upon. C3 complement component 3, C5 complement component 5, MAC membrane attack complex, PNH paroxysmal nocturnal haemoglobinuria

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Subcutaneous pegcetacoplan (EMPAVELI® in the USA and ASPAVELI® in the EU) is the first C3 inhibitor approved in the USA [5] and EU [6] for the treatment of PNH (Sect. 6). It targets C3 in the complement cascade, upstream of C5, thereby decreasing both intravascular and extravascular haemolysis [2, 3]. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of pegcetacoplan in PNH.

2 Pharmacodynamic Properties of Pegcetacoplan

Pegcetacoplan is a PEGylated pentadecapeptide C3 inhibitor [6]. The mechanism of its action is depicted in Fig 1. Pegcetacoplan binds to C3 and its activation fragment C3b, thereby inhibiting the cleavage of C3 into C3a and C3b, and the downstream effectors of complement activation, leading to regulation of MAC-mediated intravascular haemolysis and C3-mediated extravascular haemolysis (Fig 1) [3, 5, 6].

In the phase III PEGASUS trial in patients with PNH (Sect. 4.2), multiple doses of pegcetacoplan increased mean C3 concentrations from 0.94 g/L at baseline to 3.83 g/L at week 16 and PNH type II + III RBC from 66.8% to 93.9% [5, 6]. Multiple doses of pegcetacoplan also decreased PNH type II + III RBC with C3 deposition from 17.7% to 0.20% [5, 6].

The recommended dosage of pegcetacoplan was not associated with mean increases of > 20 ms in the corrected QT interval [5].

3 Pharmacokinetic Properties of Pegcetacoplan

Following a single subcutaneous infusion in healthy subjects, pegcetacoplan was gradually absorbed into the systemic circulation and reached maximum concentrations with a median time of 108–144 h (4.5–6.0 days) [5, 6]. In patients with PNH treated with pegcetacoplan 1080 mg twice weekly for 16 weeks, steady-state serum concentrations were reached in ≈ 4–6 weeks after the first dose. Exposure to pegcetacoplan increased proportionally over a dose range of 45–1440 mg [5, 6].

Based on a population pharmacokinetic analysis, the estimated bioavailability, mean volume of distribution, mean clearance and median effective elimination half-life of subcutaneous pegcetacoplan in patients with PNH is 77%, ≈ 3.9 L, 0.015 L/h and 8.0 days, respectively [5, 6]. Pegcetacoplan is expected to be metabolized by catabolic pathways into small peptides and amino acids [5, 6]. In a radiolabelled study in cynomolgus monkeys, the labelled peptide moiety was primarily eliminated via urinary excretion [6].

The pharmacokinetics of pegcetacoplan did not appear to be affected to any clinically relevant extent by sex, age (19–81 years), race (Asian vs non-Asian) or impaired hepatic or kidney function [5, 6]. There are no data on the use of pegcetacoplan in patients with end-stage renal disease requiring haemodialysis [6]. In vitro, pegcetacoplan is not an inhibitor or inducer of CYP450 isoenzymes, nor a substrate or inhibitor of the human uptake or efflux transporters [6].

4 Therapeutic Efficacy of Pegcetacoplan

The efficacy of subcutaneous pegcetacoplan for the treatment of PNH was initially established in several open-label phase I and II trials in patients with PNH who have not received a complement inhibitor (PADDOCK and PALOMINO) [7] or have previously received eculizumab (PHAROAH) [8]. In these trials, 1–2 years of treatment with pegcetacoplan provided haemolysis control and improved QOL in patients with PNH [7, 8]. Based on these findings, the efficacy of pegcetacoplan was evaluated in a 26-week, randomized, open-label, multicentre, phase III trial in complement inhibitor-naïve patients with PNH (PRINCE; Sect. 4.1) [9] and a 48-week, randomized, open-label, multinational phase III trial in complement inhibitor-treated patients with PNH (PEGASUS; Sect. 4.2) [10]. In the phase III trials discussed in this section, the dosage of subcutaneous pegcetacoplan was 1080 mg twice weekly; each dose was administered as a 20-mL subcutaneous infusion, which can be self-administered or administered by qualified research personnel [9, 10].

4.1 Complement Inhibitor-Naïve Patients

PRINCE enrolled patients aged ≥ 18 years with PNH who were naïve to complement inhibitor therapy (i.e. no treatment with eculizumab and/or ravulizumab ≤ 3 months prior to screening), and had haemoglobin levels below the lower limits of gender-specific normal (i.e. male ≤ 13.6 g/dL; female ≤ 12.0 g/dL) and lactate dehydrogenase (LDH) levels ≥ 1.5 × upper limit of normal (ULN) [9, 11, 12]. Patients were randomized to receive pegcetacoplan (n = 35) or control (supportive care; patients received blood transfusions, corticosteroids, and supplements such as iron, folate and vitamin B12; n = 18), which excluded complement inhibitor therapy, for 26 weeks. Patients in the control group had an option to switch to the pegcetacoplan group if haemoglobin levels decreased by ≥ 2 g/dL from baseline. Randomization was stratified according to the number of RBC transfusions patients had received during the 12 months prior to screening (< 4 or ≥ 4). Co-primary endpoints were haemoglobin stabilization (i.e. avoidance of a > 1 g/dL decrease in haemoglobin levels in the absence of transfusions) through week 26 and change in LDH levels at week 26 from baseline [9, 11, 12].

At week 26, pegcetacoplan was superior to control for both co-primary endpoints, with pegcetacoplan recipients achieving a significantly (p < 0.0001) higher haemoglobin stabilization (85.7% vs 0%) and greater reduction in LDH levels from baseline (−1870.5 vs −400.1 U/L) [9, 11, 12]. In the pegcetacoplan group, 65.7% of patients achieved LDH normalization (i.e. LDH levels below the ULN) through week 26 versus 0% of control recipients. Pegcetacoplan was also superior to control for secondary endpoints, which included the mean change in haemoglobin levels at week 26 from baseline (+2.9 vs +0.3 g/dL; p = 0.0019) and the percetange of transfusion-free patients (91.4% vs 5.6%; p < 0.0001). The total number of transfusion units administered was significantly (p < 0.0001) lower in the pegcetacoplan than control groups (+21 vs +59 units) [9, 11, 12]. In addition, according to a post hoc analysis, a significantly (p < 0.0001) higher percentage of pegcetacoplan than control recipients achieved complete (i.e. no RBC transfusion and haemoglobin levels of ≥ 12 g/dL) or good (i.e. no RBC transfusion and haemoglobin levels of ≥ 10 to ≤ 12 g/dL) haematological responses at week 26 (80.0% vs 5.7%) [13].

Pegcetacoplan improved QOL in complement inhibitor-naïve patients in the PRINCE trial [12, 14]. At week 26, a significantly (p = 0.0007) higher percentage of pegcetacoplan than control recipients had clinically meaningful improvements (i.e. ≥ 3-point increase from baseline) in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores (60.0% vs 11.1%) [12]. Moreover, pegcetacoplan treatment was associated with a clinically meaningful (≥ 10-point) change from baseline in global health status/QOL, functional and fatigue symptom scores on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC QLQ-C30) [14]. The improved EORTC QLQ-C30 scores were close to general population norms [14].

4.2 Complement Inhibitor-Treated Patients

PEGASUS enrolled patients with PNH who had a haemoglobin level < 10.5 g/dL despite receiving eculizumab therapy for ≥ 3 months [10]. Patients initially underwent a 4-week run-in period during which pegcetacoplan was added to their current dose of eculizumab. Afterwards, patients were randomized and received pegcetacoplan (n = 41) or eculizumab (n = 39) monotherapy for a 16-week randomized, controlled period and then entered a 32-week open-label period, in which all patients received pegcetacoplan. During the open-label period, patients switching from eculizumab to pegcetacoplan continued to receive eculizumab in addition to pegcetacoplan for the first 4 weeks. Randomization was stratified according to the number of packed RBC transfusions patients had received during the 12 months prior to screening (< 4 or ≥ 4) and their platelet count at screening (< 100,000 or ≥ 100,000 cells × 109/L) [10].

The primary endpoint was the change in haemoglobin level from baseline to week 16 [10]. If superiority for the primary endpoint was established, four key secondary endpoints were assessed for noninferiority in a hierarchical order (Table 1). Data after first transfusion were censored to minimize confounding. At baseline, patient and disease characteristics were balanced between the treatment groups [10].

Table 1 Efficacy of pegcetacoplan in adult patients with paroxysmal nocturnal haemoglobinuria with a haemoglobin level of < 10.5 g/dL despite eculizumab therapy in the phase III PEGASUS trial [10]
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Pegcetacoplan was superior to eculizumab in improving haemoglobin levels from baseline to week 16 (primary endpoint; Table 1) [10]. The increase in haemoglobin levels was seen as early as week 2 and was maintained throughout the 16-week randomized, controlled period in patients treated with pegcetacoplan. Similar results were seen in supportive analyses, which included all available data without censoring for transfusions [10].

Pegcetacoplan was also noninferior to eculizumab for the first two prespecified hierarchical secondary endpoints: the percentage of transfusion-free patients and the change in absolute reticulocyte counts (Table 1) [10]. Noninferiority was not demonstrated for the change in LDH levels, and thus noninferiority for the change in FACIT-F scores was not assessed (Table 1). However, it should be noted that the difference between the pegcetacoplan and eculizumab groups in the change in FACIT-F scores was considered to be clinically significant. Moreover, at week 16, a clinically significant change in FACIT-F scores (i.e. ≥ 3-point increase from baseline) was achieved by 73% of patients in the pegcetacoplan group versus 0% of patients in the eculizumab group, with a greater percentage of pegcetacoplan than eculizumab recipients achieving normalized levels of haemoglobin (34% vs 0%), reticulocyte counts (78% vs 3%), LDH (71% vs 15%) and total bilirubin (63% vs 8%) [10].

The clinical benefits of pegcetacoplan over eculizumab were consistently seen regardless of sex, race, age [5], baseline transfusion requirements [10, 15] and platelet counts [15]. In addition, a post hoc analysis demonstrated that a significantly greater percentage of pegcetacoplan than eculizumab recipients achieved complete (i.e. no transfusion, normal haemoglobin and no evidence of haemolysis), major (i.e. no transfusion and normal haemoglobin but with evidence of haemolysis) or good (i.e. no transfusion but with chronic mild anaemia or evidence of haemolysis) haematological responses at week 16 (73% vs 5%; p < 0.0001) [16].

Relative to eculizumab, pegcetacoplan was also associated with clinically relevant improvements in QOL, as assessed by the Linear Analog Scale Assessment (LASA) and the EORTC QLQ-C30 scores [17]. Patients with an increase in haemoglobin level of ≥ 2 g/dL and those with a larger decrease in absolute reticulocyte count and indirect bilirubin level demonstrated the greatest improvement in fatigue and physical functioning outcomes (assessed by FACIT-F and EORTC QLQ-C30 scores) [18, 19].

The improvements in clinical and haematological outcomes associated with pegcetacoplan were maintained for up to 48 weeks of treatment during the open-label period [20]. At week 48, all patients treated with pegcetacoplan (n = 77) demonstrated sustained improvements in haemoglobin levels, with > 70% of patients being transfusion-free. Patients randomized to pegcetacoplan in the randomized, controlled period and who continued pegcetacoplan during the open-label period (i.e. pegcetacoplan-to-pegcetacoplan group) maintained high mean haemoglobin levels from week 16 through to week 48 (+11.54 vs +11.30 g/dL), while patients randomized to eculizumab in the randomized, controlled period and who switched to pegcetacoplan (i.e. eculizumab-to-pegcetacoplan group) demonstrated a significant (p < 0.0001) increase in mean haemoglobin levels from week 16 to week 48 (+8.58 vs +11.57 g/dL). Improvements in other haemolysis markers, including absolute reticulocyte counts and LDH levels, were also maintained in the pegcetacoplan-to-pegcetacoplan group. In the eculizumab-to-pegcetacoplan group, a similar magnitude of improvements in absolute reticulocyte counts and LDH levels to those observed in the pegcetacoplan-to-pegcetacoplan group was seen as early as week 18, with the benefits maintained for the remainder of the open-label period [20].

Sustained improvements in QOL outcomes were also observed in the pegcetacoplan-to-pegcetacoplan and eculizumab-to-pegcetacoplan groups during the open-label period [20, 21]. At week 48, clinically meaningful improvements in FACIT-F scores (i.e. ≥ 5-point increase from baseline [22]) were maintained in the pegcetacoplan-to-pegcetacoplan group and were demonstrated in the eculizumab-to-pegcetacoplan group [20]. At this time point, the measured FACIT-F scores in both treatment groups were close to the population norms [20]. Moreover, pegcetacoplan-to-pegcetacoplan recipients exhibited sustained improvements in total LASA scores and clinically meaningful improvements (i.e. ≥ 10-point change from baseline) in global health status/QOL, functional and symptom scores on EORTC QLQ-C30 through week 48 [21]. The improvements in EORTC QLQ-C30 scores and LASA total scores were demonstrated from week 18 and week 20, respectively, in eculizumab-to-pegcetacoplan recipients and were maintained through week 48 [21].

4.3 Other Analyses

The impact of pegcetacoplan on clinical, haematological and QOL outcomes in patients with PNH was assessed in several post hoc analyses of data from PADDOCK, PALOMINO, PEGASUS and/or PRINCE [23,24,25]. Pegcetacoplan increased normalization in haemoglobin levels, LDH levels and FACIT-F scores, regardless of whether patients were naïve to complement inhibitor therapy or previously received eculizumab [23]. These improvements were also evident in the subgroup of patients with near-normal haemoglobin levels (≥ 10.0 g/dL) at baseline, with patients achieving clinically significant increases in the mean FACIT-F scores at week 16 and 48 [24]. Overall, > 50% of patients achieved and maintained complete, major or good haematological responses with pegcetacoplan [25].

5 Tolerability of Pegcetacoplan

In the clinical trials discussed in Sect. 4, subcutaneous pegcetacoplan was generally well tolerated in patients with PNH, with its tolerability profile being similar in complement inhibitor-naïve patients [12] and those previously treated with eculizumab [10]. Discussion in this section focuses largely on data available from PEGASUS (Sect. 4.2).

In PEGASUS, the tolerability profile of pegcetacoplan was similar to that of eculizumab [10]. At week 16, treatment-emergent adverse events (TEAEs) occurred in 88% of 41 pegcetacoplan recipients versus 87% of 39 eculizumab recipients, with most TEAEs being mild to moderate in severity. Injection site reactions were the most common TEAE with pegcetacoplan (37% vs 3% with eculizumab); these reactions were mostly mild in severity and occurred early, with none of the events leading to treatment discontinuation [10]. Other common (incidence ≥ 15% from either group) TEAEs in the pegcetacoplan versus eculizumab groups included infections (29% vs 26%), diarrhoea (22% vs 3%), headache (7% vs 23%) and fatigue (5% vs 15%). Serious TEAEs occurred in 17% of pegcetacoplan recipients versus 15% of eculizumab recipients and there were no reports of meningococcal infections, thrombotic events or deaths [10].

Breakthrough haemolysis was reported in 10% of pegcetacoplan recipients versus 23% of eculizumab recipients [10]. All four patients who experienced breakthrough haemolysis with pegcetacoplan had LDH elevations of > 3 × ULN; the rapid increase in LDH levels (indicative of intravascular haemolysis) occurred without identifiable triggers or detectable anti-pegcetacoplan antibodies. Three of these four patients discontinued pegcetacoplan treatment and switched back to eculizumab treatment [10].

No new safety signals were identified during the open-label period of PEGASUS [20]. At week 48, TEAEs occurred in 87% of 38 pegcetacoplan-to-pegcetacoplan recipients and 95% of 39 eculizumab-to-pegcetacoplan recipients, with most TEAEs being mild or moderate in severity. The most commonly (≥ 10%) reported TEAEs in all patients treated with pegcetacoplan included infections and infestations (55%), injection site reactions (26%), haemolysis (20%), diarrhoea (13%), fatigue (10%), headache (10%) and cough (10%). During the open-label period, the most common infections with pegcetacoplan included nasopharyngitis (16%) and upper respiratory tract infection (10%); there were no cases of meningococcal infections. The incidence of injection site reactions decreased with continued treatment with pegcetacoplan. Overall, 18 patients experienced serious TEAEs, three patients experienced sepsis, two patients experienced thrombosis (deemed unrelated to pegcetacoplan) and nine patients discontinued treatment due to a TEAE [20].

Throughout the open-label period, 23% of patients experienced an acute investigator-reported haemolytic event, including haemolysis, haemolytic anaemia and intravascular haemolysis [20]. Of the 15 patients who had haemolysis, 80% received increased dose of pegcetacoplan, and the benefits were demonstrated in 50% of patients receiving the increased dose. The exposure-adjusted rate of haemolysis in patients treated with pegcetacoplan was lower in the open-label period versus the randomised, controlled period (33.5 vs 40.6 events per 100 patient-years) [20].

According to a post hoc analysis of data from PRINCE and PEGASUS, pegcetacoplan improved D-dimer normalization (i.e. a marker of thrombosis risk) and reduced the frequency of thrombotic events in complement inhibitor-naïve patients and in patients previously treated with eculizumab [26]. This finding was supported by week 48 interim results from an ongoing, long-term extension study, indicating that pegcetacoplan may have a sustainable beneficial effects on thrombosis risk reduction [27].

Like all therapeutic proteins, pegcetacoplan has the potential for immunogenicity. Anti-drug antibody (ADA) incidence was low and the presence of ADA had no noticeable impact on pharmacodynamics, pharmacokinetics, efficacy and safety of pegcetacoplan [6]. In PEGASUS, two of 80 patients developed anti-pegcetacoplan peptide antibodies after 16 weeks of treatment with pegcetacoplan. Both patients also tested positive for neutralizing antibody; however, the presence of neutralizing antibody had no apparent impact on pharmacokinetics or clinical efficacy of pegcetacoplan [6].

6 Dosage and Administration of Pegcetacoplan

In the USA, pegcetacoplan is indicated for the treatment of adult patients with PNH [5]. In the EU, pegcetacoplan is indicated for the treatment of adult patients with PNH who are anaemic after ≥ 3 months of treatment with a C5 inhibitor [6]. The recommended dosage of pegcetacoplan is 1080 mg twice weekly, which is administered as a subcutaneous infusion using a commercially available syringe system infusion pump (with a reservoir of up to 20 mL). Pegcetacoplan treatment should be initiated under the guidance of a healthcare professional. If a healthcare professional determines that it is appropriate, pegcetacoplan can be administered by a patient or caregiver after proper training [5, 6].

During pegcetacoplan therapy, patients should be regularly monitored for signs and symptoms of haemolysis [5, 6]. If a patient has a LDH level of > 2 × ULN, the pegcetacoplan dosage can be increased to 1080 mg every 3 days; LDH levels should be monitored twice weekly for ≥ 4 weeks after dosage adjustment. [5, 6].

Due to its mechanism of action, pegcetacoplan may increase the risk of serious, life-threatening or fatal infections caused by encapsulated bacteria, including Neisseria meningitides, Streptococcus pneumonia and Haemophilus influenza [5, 6]. The US prescribing information for pegcetacoplan carries a black box warning regarding the risk of serious infections caused by encapsulated bacteria [5]. To mitigate this risk, all patients must be vaccinated against encapsulated bacteria ≥ 2 weeks before starting pegcetacoplan and should be monitored for signs and symptoms of infections during treatment with pegcetacoplan [5, 6]. If an infection caused by encapsulated bacteria is suspected, patients should be treated with appropriate antibiotics [5, 6].

Local prescribing information should be consulted for detailed information regarding dosage recommendation when switching from C5 inhibitors, administration procedures, recommended vaccination and prophylaxis, warnings and precautions, drug interactions, and use in specific populations.

7 Current Status of Pegcetacoplan in Paroxysmal Nocturnal Haemoglobinuria

The current standard of care for the management of PNH includes the use of C5 inhibitors eculizumab and ravulizumab [1, 28]. Although C5 inhibitors provide substantial clinical benefits, many patients continue to experience haemolysis, unresolved anaemia and require frequent blood transfusions despite therapy (Sect. 1) [3, 4]. To improve disease control, pegcetacoplan has been developed and approved in the USA and EU as the first C3-targeted complement inhibitor for patients with PNH. By targeting C3, pegcetacoplan has the potential to control both intravascular and extravascular haemolysis (Sect. 2). The UK National Institute for Health and Care Excellence recommends pegcetacoplan as an option for treating PNH in adults who are anaemic after ≥ 3 months of treatment with a C5 inhibitor [29].

Subcutaneous pegcetacoplan was effective in providing haemolysis control and improving QOL in patients with PNH (Sect. 4). In the PRINCE trial, pegcetacoplan was superior to control in terms of normalizing haemoglobin levels and reducing LDH levels, as well as improving QOL to a clinically meaningful extent in patients with PNH who were naïve to complement inhibitor therapy (Sect. 4.1). Similarly, in the PEGASUS trial, pegcetacoplan was superior to eculizumab in improving haemoglobin levels and was noninferior to eculizumab in terms of other clinical and haematological parameters (i.e. the percentage of transfusion-free patients and the change in absolute reticulocyte count) in patients with PNH who were anaemic despite eculizumab therapy (Sect. 4.2). Relative to eculizumab, pegcetacoplan also improved QOL, especially reduced fatigue symptoms, to a clinically meaningful extent. The clinical benefits of pegcetacoplan were maintained for up to 48 weeks of treatment (Sect. 4.2). Further data on real-world experience of pegcetacoplan would be of interest.

Pegcetacoplan was generally well tolerated in patients with PNH, regardless of whether patients were naïve to complement inhibitor therapy or were previously treated with eculizumab (Sect. 5). Overall, the tolerability profile of pegcetacoplan was similar to that of eculizumab, with most TEAEs being mild to moderate in severity. The most common TEAEs with pegcetacoplan were injection site reactions, which were mostly mild and decreased with continued treatment as patients became more comfortable and experienced with self-administration [30]. The incidence of injection site reactions was comparable to that observed with other drugs that are administered similarly to pegcetacoplan [30]. In addition, encapsulated bacterial infections are a potential safety concern with pegcetacoplan due to its mechanism of action; however, there were no cases of meningococcal infections in the phase III trials (Sect. 5). Although these findings are encouraging, long-term data on the incidence of infections would be interest. Further safety data from the long-term extension phase III trial are also awaited with interest.

Haemolytic events during pegcetacoplan treatment are of noteworthy concern owing to the potential for more severe haemolysis due to a greater accumulation of PNH red cells with proximal complement inhibition [20, 31]. It is recommended to closely monitor patients for signs and symptoms of breakthrough haemolysis during pegcetacoplan treatment. In the event of breakthrough haemolysis, immediate RBC transfusion, pegcetacoplan dose adjustment or short-term use of eculizumab should be considered to control intravascular haemolysis and prevent serious clinical consequences [20, 31].

In the absence of direct comparisons between pegcetacoplan and ravulizumab, indirect comparison analyses suggest pegcetacoplan has favourable efficacy compared with ravulizumab in terms of clinical, haematological, and QOL outcomes in complement inhibitor-treated [4] and -naïve patients [32]. However, given the indirect nature of the comparisons, these findings should be interpreted with caution.

Despite the dosing schedule of eculizumab and ravulizumab being less frequent, pegcetacoplan offers increased flexibility to patients as it can be self-administered subcutaneously at home following proper training, compared with intravenous administration of eculizumab and ravulizumab in a hospital setting [3, 7]. Of note, although the compliance rate within a clinical trial is often higher than that of real world, the average compliance rate of pegcetacoplan in the PEGASUS and PRINCE trials was > 99%, which exceeded the compliance rates found for other self-administered oral medications for chronic conditions in published literature (13–89%) [33].

Although to be confirmed in the real world, a Markov cohort using PEGASUS data indicates that, in the UK healthcare and social services setting, pegcetacoplan is associated with lower lifetime costs and greater quality-adjusted life years versus ravulizumab in patients with PNH who are anaemic despite eculizumab therapy [34]. In a cost per responder analysis, based on US payer perspective and efficacy data from PEGASUS, PADDOCK/PALOMINO, pegcetacoplan was predicted to be more cost effective than eculizumab, with a lower cost per responder for achieving good or good-to-complete haematological response [35]. Furthermore, in a budget-impact analysis, the addition of pegcetacoplan to a US health plan substantially lowered healthcare costs by reducing costs for drug acquisition, blood administration, transfusions and breakthrough haemolysis [36].

While further clinical experience of pegcetacoplan would be beneficial, current evidence indicates that pegcetacoplan is a valuable treatment option for adults with PNH.

Data Selection Pegcetacoplan: 136 records identified

Duplicates removed

37

Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial)

14

Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials)

49

Cited efficacy/tolerability articles

22

Cited articles not efficacy/tolerability

14

Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were Pegcetacoplan, Aspaveli, EMPAVELI, Paroxysmal nocturnal hemoglobinuria. Records were limited to those in English language.

Searches last updated 31 October 2022.