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Safety and efficacy of pegcetacoplan in paroxysmal nocturnalhemoglobinuria

Raymond SM Wong1,✉
1Sir Y.K. Pao Centre for Cancer and Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong
✉

Email:raymondwong@cuhk.edu.hk

Roles

Raymond SM Wong:Conceptualization, Writing original draft, Writing review editing

Received 2022 Jan 15; Accepted 2022 Jul 4; Collection date 2022.

© The Author(s), 2022

This article is distributed under the terms of the Creative CommonsAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) whichpermits non-commercial use, reproduction and distribution of the workwithout further permission provided the original work is attributed asspecified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).

PMCID: PMC9340389  PMID:35923770

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologicdisease characterized by complement-mediated hemolysis, thrombosis, and variousdegrees of bone marrow dysfunction. Until recently, C5 inhibition witheculizumab or ravulizumab represented the only therapies approved for patientswith PNH by the United States Food and Drug Administration (US FDA). AlthoughC5-inhibitors reduce PNH-related signs and symptoms, many patients continue toexhibit persistent anemia and require frequent blood transfusions. In May 2021,pegcetacoplan became the third US FDA-approved treatment for adults with PNH,and the first to target C3, a complement component upstream of C5. The novelstrategy of inhibiting proximal complement activity with pegcetacoplan controlsC5-mediated intravascular hemolysis and prevents C3-mediated extravascularhemolysis. Here, we review the results from multiple pegcetacoplan clinicalstudies on the efficacy and safety of pegcetacoplan treatment in adults withPNH. This review summarizes findings from three studies incomplement-inhibitor-naïve patients with PNH (PADDOCK [phase Ib], PALOMINO[phase IIa], PRINCE [phase III; pegcetacoplan versus standard treatmentexcluding complement-inhibitors]), and one phase III study (PEGASUS) thatcompared eculizumab to pegcetacoplan in patients who remained anemic (hemoglobinlevels < 10.5 g/dL) despite stable eculizumab treatment (⩾3 months). Thesestudies found that pegcetacoplan contributed to superior improvements in primaryand secondary endpoints related to hemoglobin levels and other hematologicparameters and provided effective management of anemia and anemia-relatedcomplications (i.e. transfusion burden, reticulocyte production, and fatigue).Furthermore, we summarize results from the 32-week open-label period from thePEGASUS trial, which confirmed the long-term safety and durable efficacy ofpegcetacoplan as demonstrated by sustained improvements in clinical andhematologic outcomes in pegcetacoplan-treated patients. Pegcetacoplan isapproved for the treatment of adults with PNH in the United States (Empaveli™)and for adult patients who remain anemic after at least 3 months of stableC5-inhibitor therapy in the European Union (Aspaveli®) and Australia(Empaveli; also approved for patients intolerant to C5-inhibitors).

Keywords: anemia, complement-inhibitor, hemolysis, paroxysmal nocturnal hemoglobinuria, pegcetacoplan, quality-of-life

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic diseasecharacterized by complement-mediated hemolysis, thrombosis, and mild-to-severe bonemarrow dysfunction.1 While its global prevalence is understudied,2 PNH has been estimated to affect as many as 16 individuals per millionworldwide.3,4A 2020 analysis of data from the International PNH Registry – a worldwide,observational, non-interventional repository of safety, efficacy, andquality-of-life (QoL) data from patients with confirmed PNH – revealed that themedian age at disease onset is 35.5 years old.5 Prior to the development of eculizumab, and later ravulizumab, to inhibitterminal complement activation with C5 blockade, there were no United States Foodand Drug Administration (US FDA)-approved therapies for PNH. Although C5-inhibitor(C5i) therapy has improved outcomes for patients with PNH,6–9 many C5i-treated patientsexperience residual complement-mediated hemolysis, unresolved anemia, andanemia-related complications (i.e. transfusion burden, fatigue, and impairedQoL).10–12

Pegcetacoplan is the first C3-targeted complement-inhibitor that was approved for thetreatment of adults with PNH by the US FDA (May 2021)13 and for adults who remain anemic despite stable treatment with C5i for atleast 3 months by the European Medicines Agency (EMA, December 2021)14 and the Australian Therapeutic Goods Agency (February 2022; also approved forpatients intolerant to C5i).15 Pegcetacoplan provides a novel approach for preventing complement-mediatedhemolysis by targeting the proximal complement protein C3, a component that isupstream of C5. Thus, C3 inhibition with pegcetacoplan can provide control over bothproximal and terminal complement activation and prevent extravascular andintravascular hemolysis, respectively. Here we review the results from several earlyand late phase clinical studies conducted to assess the safety and efficacy ofpegcetacoplan in complement-inhibitor-naïve patients with PNH and in anactive-comparator study with eculizumab among patients who remained anemic despitestable eculizumab treatment. We also provide a brief overview of the pathophysiologyand clinical manifestations of PNH, and background information on C5-inhibitingtherapies for PNH.

An overview of PNH pathophysiology

PNH is caused by somatic mutations in the X-linked phosphatidylinositol glycan classA (PIGA) gene locus of hematopoietic stem cells.16,17PIGA encodes one of the several proteins involved in the first stepof glycosylphosphatidylinositol (GPI) anchor biosynthesis.16,18 While a number ofPIGA mutations have been observed in patients with PNH, mostare located in exon 2 of the gene and result in the severe deficiency or absence ofGPI anchors.19 GPI anchors integrate more than 20 different proteins, including thecomplement-inhibitor proteins CD55 and CD59, in the membrane of hematopoietic cells,resulting in their expression at the cell surface.20

CD55 and CD59 cell surface expression protects red blood cells (RBCs) from lysismediated by distinct complement molecules and the membrane attack complex (MAC).CD55, or ‘decay-accelerating factor’, regulates the proximal complement cascade bypreventing the formation of membrane-bound C3 convertase, accelerating C3 convertasedecay, and ultimately inhibiting the conversion of C3 into C3b and C3a.21,22 CD59 preventsterminal complement activity by blocking the aggregation of C9 with other componentmolecules (C5b, C6, C7, C8) necessary for MAC formation, thereby preventingintravascular hemolysis.22,23 Deficiency or absence of CD55 and CD59 thus results in chroniccomplement-mediated hemolysis in patients with PNH, and a greater than 90% reductionin the lifespan of PNH RBCs as compared to normal RBCs.24

Complement can be activated through multiple pathways (i.e. classical, alternative,and lectin) that converge at the complement component C3, which is the centralprotein in the complement cascade.25 C3 is cleaved into the anaphylatoxin, C3a, and the opsonin, C3b. C3b plays acentral role in complement-mediated hemolysis in PNH by contributing to theopsonization of clonal RBCs (by C3b and its degradation products)25 leading to extravascular hemolysis and to the formation of C5 convertase,leading to C5b generation, MAC formation, and intravascular hemolysis (Figure 1).22 The chronic hemolysis associated with PNH manifests distinctly depending onwhether it is due to intravascular or extravascular hemolysis. Intravascularhemolysis presents clinically as decreased hemoglobin levels, increased serum levelsof lactate dehydrogenase ([LDH] an enzyme released from lysed RBCs)e and bilirubin(product of heme catabolism), and an elevated absolute reticulocyte count (ARC) dueto the bone marrow’s compensatory production of RBCs.1,26 Residual intravascularhemolysis in patients receiving C5i therapy may occur for several reasons, includingpharmacokinetic breakthrough (e.g. due to insufficient C5i dosing), pharmacodynamicbreakthrough (i.e. complement activation in the setting of a complement-amplifyingcondition), or rare C5 genetic polymorphisms.27 C3-mediated extravascular hemolysis can occur in patients with PNH despiteC5i therapy and has a slightly different clinical presentation in which levels ofbilirubin and ARC, but not necessarily LDH, are increased.28–31

Figure 1.

Figure 1.

The complement cascade and complement-inhibitors approved by the US FDA, EMA,and Australian Therapeutic Goods Agency for the treatment of PNH[Pegcetacoplan (P); Eculizumab (E); and Ravulizumab (R)]. By inhibiting C3and C3b, pegcetacoplan exerts broad inhibition of the complement cascade,reduces the risk of thrombosis, and prevents both intravascular hemolysisand extravascular hemolysis. C5-inhibitors eculizumab and ravulizumab canreduce thrombosis and intravascular hemolysis but do not addressextravascular hemolysis.

EVH, extravascular hemolysis; IVH, intravascular hemolysis; MAC, membraneattack complex; PNH, paroxysmal nocturnal hemoglobinuria; RBCs, red bloodcells.

*PNH RBCs can become opsonized by C3b and its degradation products, iC3b andC3dg, which target PNH RBCs for the destruction byphagocytosis/extravascular hemolysis in the liver and spleen.25 The relative role of C3b, iC3b, and C3dg in promoting extravascularclearance of PNH RBCs is still under investigation.

Clinical manifestations of PNH

The classification of PNH proposed by the International PNH Interest Group includesthree subtypes:32 (1) classical PNH, which includes hemolytic and thrombotic patients who haveevidence of PNH in the absence of another bone marrow failure disorder; (2) PNH inthe context of other primary bone marrow disorders, such as aplastic anemia ormyelodysplastic syndrome; and (3) subclinical PNH, in which patients have small PNHclones but no clinical or laboratory evidence of hemolysis or thrombosis. Thesesubtypes are associated with different implications for the QoL of patients withPNH. While patients with subclinical PNH may lead normal lives, patients withclinically significant disease experience signs and symptoms of PNH that can bedebilitating and impact their QoL.

The symptomatology of patients with PNH is well-documented in the International PNH Registry.5 Substantial proportions of enrolled patients exhibited a history ofphysician-reported PNH-related symptoms at baseline; fatigue was the most common(80.0%), while other symptoms included dyspnea (45.3%), hemoglobinuria (45.0%),abdominal pain (35.2%), dysphagia (16.5%), and erectile dysfunction (24.2% of male registrants).5 In the overall population of patients with PNH, patient-reported scores fromQoL assessments based on the psychometrically validated Functional Assessment ofChronic Illness Therapy (FACIT)-Fatigue and European Organisation for the Researchand Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) globalhealth/QoL scales demonstrated impaired QoL and considerable fatigue, with medianscores of 34.0 and 58.3, respectively.5 Normative mean reference scores for the general adult population have beenreported on the FACIT-Fatigue (43.6)33 and EORTC QLQ-C30 global health/QoL (75.7)34 scales, with a ⩾ 3-point decrease in FACIT-Fatigue scores35 and ⩾ 10-point decrease in EORTC QLQ-C30 global health/QoL scores36,37 consideredclinically meaningful.

C5-inhibiting therapies for PNH and unmet needs

Prior to the development of complement-inhibitors, there were no US FDA-approvedtherapies for patients with PNH. Clinical management of PNH was primarilysupportive, with a median survival after diagnosis of approximately 10 years forpatients with clinically significant PNH.38 Most PNH-related deaths were due to thrombotic events.38,39

The C5i, eculizumab (a monoclonal antibody reactive against C5; AlexionPharmaceuticals, Inc.), was the first therapy to be US FDA-approved for treatment ofpatients with PNH in March 2007. Phase II/III clinical trials of eculizumab inpatients with PNH demonstrated its long-term efficacy and safety, with resultsshowing sustained improvements in hemolytic markers, such as LDH, hemoglobinuria,and transfusion requirements, and patient-reported QoL measures.40,41 These trialsalso showed lower rates of life-threatening thrombotic events and survivalcomparable to that of age- and sex-matched controls without PNH.42 There are, however, several clinical and practical limitations to eculizumabtherapy. The indefinite 2-week intravenous dosing schedule due to the drug’s shorthalf-life (one reason for eculizumab’s high cost of therapy) can be inconvenient forpatients by increasing the frequency of infusion clinic visits.40 Many patients also require doses higher than those approved for PNH, withnearly half of all patients in a recent study receiving higher than thelabel-recommended 900 mg biweekly maintenance dose.43 These findings are of particular concern due to the demonstrated temporalassociation with eculizumab dosing, suboptimal C5 inhibition, and breakthrough hemolysis.44

US FDA approval of the next therapy for patients with PNH, the C5i ravulizumab(Alexion Pharmaceuticals, Inc.), did not occur until December 2018. Ravulizumab isderived from the same antibody clone as eculizumab, but features amino acidsubstitutions that extend its half-life.45 Ravulizumab provides patients with therapeutic benefits similar to those ofeculizumab while reducing the incidence of breakthrough hemolysis events8,9,44 and enabling a moreconvenient 8-week dosing schedule compared to eculizumab.40 Phase III trial data demonstrated similar safety profiles for ravulizumab andeculizumab,8,9yet ravulizumab did not provide a novel mechanism for inhibiting complement-mediatedhemolysis, resulting in a C5i therapy for PNH that shared many limitations with itspredecessor.

While C5i therapies have improved the clinical management of PNH, there are severallimitations associated with the use of these treatments. A considerable proportionof patients treated with C5i therapy continue to exhibit signs and symptoms ofongoing hemolysis.10,46 Persistent anemia may occur in C5i-treated patients with PNHdue to comorbidities associated with bone marrow failure (i.e. aplastic anemia andmyelodysplastic syndromes).47,48 Studies have also suggested that ongoing hemolysis may occur inC5i-treated patients due to C5i unmasking a low-level of additional extravascularhemolysis in patients with PNH. It has been suggested that this additional low-levelextravascular hemolysis occurs when PNH RBCs are not destroyed by intravascularhemolysis in the presence of C5i, leaving these excess PNH RBCs susceptible to C3bopsonization and extravascular hemolysis.28–30,46,49 In addition, residualintravascular hemolysis in the presence of sufficient C5i dosing can occur for anumber of reasons including (1) the presence of complement-amplifying conditions,such as major surgery, infection, or third trimester pregnancy;50 (2) existing comorbidities, such as atypical hemolytic uremic syndrome (aHUS);51 or (3) evasion of C5i through a C3 bypass mechanism.52 The C3 bypass mechanism occurs with dense C3b opsonization on RBCs thatinduces a C5b-like conformation in C5 leading to C5 convertase-independent MAC formation.52 This bypass mechanism further highlights the need for pharmacotherapies forPNH that directly inhibit C3b opsonins.

Major concerns with ongoing hemolysis with C5i therapies are related to theconsequences of persistently low hemoglobin levels/anemia and chronic transfusiondependence. Many patients with PNH receiving C5i therapy fail to achieve hemoglobinnormalization with hemoglobin levels above the lower limit of normal(LLN).10–12 Persistentlylow hemoglobin levels and unresolved anemia can result in multi-organ damage due toreduced blood oxygen capacity53 and contribute to fatigue and impairments in QoL.10,54 More than 75% of C5i-treatedpatients with PNH report unresolved fatigue, and many patients report impairments inoverall QoL, decreased productivity, and activity impairment. Relatedly, persistentanemia can also lead to chronic transfusion dependence, which is associated withcomplications such as iron overload.55 Notably, more than half of the patients with PNH receiving C5i therapy reportongoing transfusion requirements.10

Additional concerns regarding the clinical utility of C5i therapies includehepatotoxicity and the development of bilirubin gallstones with long-term use.Although further pharmacovigilance research is required to evaluate hepatotoxicityin C5i-treated patients with PNH, hepatoxicity has been observed among some aHUSpatients treated with eculizumab who displayed elevated liver enzyme levelsfollowing eculizumab treatment.56,57 Furthermore, increasedbilirubin levels due to unresolved extravascular hemolysis in C5i-treated patientswith PNH can increase the likelihood of developing bilirubin gallstones.58

The development of pegcetacoplan

The inability of C5i treatment to thoroughly control intravascular hemolysis andprevent extravascular hemolysis in patients with PNH has driven the development ofpharmacotherapies that target alternative molecules in the complement cascade, suchas C3 with pegcetacoplan.59 Research on C3 as a possible therapeutic target has been conducted over thepast several decades and is punctuated by the development of the first peptidicC3-inhibitor, compstatin.60–62 Pegcetacoplan(Empaveli™/Aspaveli®; FDA/EMA), a PEGylated and bivalent variation ofa second-generation compstatin analog, was developed and validated by ApellisPharmaceuticals, Inc. Pegcetacoplan consists of two 15-amino acid cyclic peptidesconjugated to a linear polyethylene glycol molecule to increase its half-life.

Pegcetacoplan prevents downstream C3 activity by binding C3 and its cleavage product,C3b; thus inhibiting C3 activation by its convertase, C3b opsonization of RBCs, andC3b’s role in the downstream activation of C5 by its convertase (Figure 1).63–65 As pegcetacoplan targets thecomplement cascade upstream of C5 (targeted by ravulizumab and eculizumab), itprovides more complete hemolysis protection by reducing terminal complement-mediatedintravascular hemolysis and preventing C3b-associated extravascular hemolysis (Figure 1).13,64,66 Comprehensivecontrol of complement-mediated hemolysis with pegcetacoplan enables substantialimprovements in key PNH outcomes including improvements in hematologic parameters(hemoglobin, LDH, ARC, bilirubin) and anemia-related complications (transfusionrequirements, fatigue, and QoL). These data are discussed in the following section,which presents results from multiple pegcetacoplan clinical studies amongcomplement-inhibitor-naïve patients and patients who demonstrated insufficientresponse to stable eculizumab treatment.

The safety and efficacy of pegcetacoplan in clinical trials

PHAROAH

PHAROAH (NCT02264639) was a phase Ib, open-label, prospective, non-randomized,single and multiple ascending dose trial conducted across seven clinical sitesin the United States.64,67 Key eligibility criteria included patients with PNHaged ⩾ 18 years, weighing > 55 kg, with a hemoglobin level < 10 g/dLdespite ⩾ 3 months of treatment with eculizumab.64 The trial consisted of four cohorts, with patients being able toparticipate in multiple cohorts.64 Initially, pegcetacoplan (25–360 mg/day dosing range depending on thecohort) was administered subcutaneously by trained research personnel.64 Patients transitioned to self-administered subcutaneous pegcetacoplaninfusion following the introduction of an ambulatory syringe pump and wererequired to continue their regular eculizumab dosing regimen throughout the trial;64 A total of nine patients were enrolled in the trial; four patientscompleted the 2-year trial; enrolled in the extension study, and discontinuedeculizumab between Day 457 and Day 626.64

The PHAROAH trial’s primary endpoints were the number and severity oftreatment-emergent adverse events (TEAEs) and pegcetacoplan pharmacokineticparameters.64,67 Overall, 427 TEAEs were reported over the 2-year trialperiod: 68 TEAEs were considered possibly related to pegcetacoplan, with 48 ofthese TEAEs related to the drug injection site.64 Twelve serious adverse events (SAEs) were reported in two patients (ofwhich eight were TEAEs). Steady-state serum concentration of pegcetacoplan wasreached in most patients approximately 6–8 weeks after dosing initiation,although some patients may have reached steady-state serum concentration between4 and 6 weeks.64

Pegcetacoplan treatment in PHAROAH increased hemoglobin levels (at the 2-yeartimepoint, three of four patients exhibited hemoglobin levels within the normalrange of 11.1–15.9 g/dL) and reduced ARC, LDH, and total bilirubin. The majorityof PHAROAH patients (three of four) demonstrated a clinically meaningful changeof a ⩾ 3-point35 improvement in score on the FACIT-Fatigue scale.64 Transfusion avoidance was achieved in all patients who completed the study.64 In addition, pegcetacoplan increased the clonal distribution of type IIand III PNH RBCs and decreased C3 fragment deposition on the surface of these cells.64

Overall, the PHAROAH trial demonstrated that treatment with pegcetacoplan wasgenerally well-tolerated and improved hematological outcomes by achieving broadcontrol of hemolysis through C3 inhibition in a small patient population thatwas initially receiving eculizumab.

PADDOCK and PALOMINO

Two open-label trials were initiated to investigate whethercomplement-inhibitor-naïve patients with PNH could equally benefit frompegcetacoplan: PADDOCK (NCT02588833), a phase Ib, multiple-ascending dose pilottrial with two cohorts, and PALOMINO (NCT03593200), a phase IIa, multiple-dose,single cohort trial using the same protocol and dosing schedule as Cohort 2 ofthe PADDOCK trial.68–70 Bothtrials enrolled patients with PNH aged ⩾ 18 years, PNH white blood cell clonesize > 10%, platelet count > 30,000/mm3, absolute neutrophilcount > 500/mm3, LDH level ⩾ 2 times the upper limit of normal(ULN) at the screening visit, and a history of receiving at least one bloodtransfusion within 12 months prior to screening.68,69 Patients who had receivedprior eculizumab treatment were excluded from both trials. Pegcetacoplan(180–360 mg/day dosing range) was administered subcutaneously or viasubcutaneous infusion when the dosing volume was > 3 ml. The PADDOCK trialenrolled 3 patients in Cohort 1 and 20 patients in Cohort 2; 1 patient enteredboth cohorts.68 The PALOMINO trial enrolled 4 patients.68

The PADDOCK and PALOMINO trials’ primary efficacy endpoints were change frombaseline in LDH, haptoglobin, and hemoglobin levels. In both trials,68 improvements were observed at Day 365 after initiation of pegcetacoplandosing in LDH (from > 8 times the ULN to < 2 times the ULN), hemoglobin(from below the LLN to within normal range), and haptoglobin levels (Table 1).Improvements were also observed for ARC, total bilirubin levels, and meanFACIT-Fatigue scores (i.e. a clinically meaningful improvement of ⩾ 3-points)35 in both trials (Table 1).68 After initiation of pegcetacoplan, 65% of PADDOCK patients and 100% ofPALOMINO patients were transfusion-free (Table 1).68 Categorized hematologic response to treatment for patients in thecombined PADDOCK and PALOMINO trials, per criteria defined by Risitanoet al.,59 was as follows: Week 16 – good-to-complete 75.0%, partial 4.2%, minor8.3%, no response 4.2%; Week 48 – good-to-complete 62.5%, partial 20.8%, minor4.2%, no response 0.0%.74

Table 1.

Key endpoints from the pegcetacoplan phase I (PADDOCK),68 phase II (PALOMINO),68 and phase III (PEGASUS66,71,72 and PRINCE73) clinical trials.

PADDOCKa
(Day 365)68		PALOMINOa
(Day 365)68		PEGASUSa
(Week 16)66,71		PEGASUSa
(Week 48)72		PRINCEa
(Week 26)73
PegcetacoplanPegcetacoplanPegcetacoplanEculizumabPegcetacoplanEculizumabPegcetacoplanControl treatmentb
Hemoglobin, mean (SD), g/dL
(NRR: females 12–16;males 13.6–18)		12.1 (2.0)13.0 (2.2)11.5 (2.0)8.6 (1.0)11.3 (1.8)11.6 (2.2)12.8 (2.1)9.8 (2.4)
LDH, mean (SD), U/L
(PADDOCK/PALOMINO NRR: 120–250;PEGASUS NRR: 113–226)		306.5 (324.7)226.0 (27.0)189.0 (78.1)353.0 (477.5)222.7 (141.1)224.1 (133.5)204.6 (90.0)1535.0 (751.6)
ARC, mean (SD), × 109/L
(PADDOCK/PALOMINONRR: 10–110; PEGASUS NRR: 30–120)		96.4 (33.4)94.0 (26.9)77.0 (26.6)221.0 (88.7)80.0 (26.8)94.0 (50.1)
Total bilirubin, mean (SD), mg/dL
(PADDOCK/PALOMINONRR: 3–20; PEGASUS NRR: 1.7–18.8)		13.9 (5.6)9.3 (8.2)
FACIT-Fatigue, mean (SD)
(Population norm: 43.6)33		42.5 (8.5)47.0 (2.5)41.8 (9.6)30.6 (11.8)40.6 (10.1)42.5 (8.7)45.3 (7.3)39.6 (10.3)
Haptoglobin, mean (SD), g/L
(NRR: 0.14–2.58)		0.1 (0.1)0.18 (0.2)
Freedom from transfusionsc,n (%)13 (65.0)4 (100.0)35 (85.4)6 (15.4)30 (73.0)28 (78.0)32 (91.4)1 (5.6)
Clonal distribution of type II and type III PNH RBCs, % mean(SD)84.0 (21.0)93.0 (6.3)93.9 (6.4)62.6 (26.0)
C3 deposition on type II and type III PNH RBCs, % mean(SD)0.4 (0.6)0.1 (0.1)0.2 (0.3)16.9 (15.5)

ARC, absolute reticulocyte count; FACIT-Fatigue, FunctionalAssessment of Chronic Illness Therapy Fatigue scale; LDH, lactatedehydrogenase; NRR, normal reference range; PNH, paroxysmalnocturnal hemoglobinuria; RBC, red blood cell; SD, standarddeviation.

a

Data included in this table represent any publicly available data forthese trials at the time of submission of this review article.

b

Supportive treatment, including blood transfusions, anticoagulants,corticosteroids, and supplements (iron, folate, and vitaminB12).

c

Also known as transfusion avoidance.

Overall, 143 TEAEs were reported in 19 subjects (86.4%) in both PADDOCK cohorts(Table 2); 35TEAEs were considered either possibly or probably related to pegcetacoplan.68 In PADDOCK, 13 SAEs were reported:68 three SAEs (aplastic anemia, abdominal neoplasm, and hypersensitivity)led to pegcetacoplan discontinuation in three subjects, with two of these SAEs(aplastic anemia [fatal, but considered not related to pegcetacoplan] andabdominal neoplasm) resulting in trial discontinuation. In PALOMINO, 60 TEAEswere reported in three (75.0%) patients (Table 2); 52 of these TEAEs wereconsidered possibly related to pegcetacoplan.68 One SAE (a rib fracture) was reported for PALOMINO but was not consideredto be related to pegcetacoplan treatment. For both trials, no TEAEs led todeath, pegcetacoplan discontinuation, or trial discontinuation.

Table 2.

Reported AEs from the pegcetacoplan phase I (PADDOCK),68 phase II (PALOMINO),68 and phase III (PEGASUS66,72 and PRINCE73) clinical trials.

AEs
No. of patients (%)		PADDOCK
(Day 365)68		PALOMINO
(Day 365)68		PEGASUS
(Week 16)66		PEGASUS
(Week 48)72		PRINCE
(Week 26)73
Pegcetacoplan
N = 22		Pegcetacoplan
N = 4		Pegcetacoplan
N = 41		Eculizumab
N = 39		Pegcetacoplan-to-pegcetacoplan
N = 38		Eculizumab-to-pegcetacoplan
N = 39		Pegcetacoplan
N = 46		Control treatmenta
N = 18
Any TEAE19 (86)3 (75)36 (88)34 (87)33 (87)37 (95)33 (72)12 (67)
Any serious AE7 (32)1 (25)7 (17)6 (15)8 (21)10 (26)4 (9)3 (17)
Injection site reactions6 (27)b1 (25)b15 (37)1 (3)7 (18)13 (33)14 (30)0 (0)
Infections and infestationsc12 (29)10 (26)21 (55)21 (54)
Meningitis0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Thrombosis0 (0)0 (0)0 (0)1 (3)d1 (3)d0 (0)0 (0)

AE, adverse event; no., number; TEAE, treatment-emergent adverseevents.

a

Supportive treatment including blood transfusions, anti-coagulants,corticosteroids, and supplements (iron, folate, vitamin B12).

b

Terminology used: general disorders and administration sitereactions.

c

Infections and infestations were defined as upper respiratory tractinfection, urinary tract infection, chronic sinusitis,diverticulitis, pyelonephritis acute, appendicitis, bartholinitis,biliary sepsis, breast abscess, bronchitis, cystitis, device-relatedsepsis, fungal skin infection, gastroenteritis, herpes virusinfection, undefined infection, and malaria.

d

Both thrombotic events (one in the setting of diffuse large B-celllymphoma, one in the setting of pneumonia infection in the presenceof renal failure) were deemed unrelated to pegcetacoplan; neitherevent resulted in study discontinuation.

Overall, these two early phase clinical trials demonstrated the efficacy andsafety of pegcetacoplan in complement-inhibitor-naïve patients, supportingfurther evaluation of pegcetacoplan in this patient population in the phase IIIPRINCE trial.

PEGASUS

Sixteen-week randomized controlled period

The PEGASUS trial (NCT03500549) – a phase III, randomized, open-label,active-comparator controlled trial conducted across 44 clinical sitesworldwide – assessed the efficacy and safety of pegcetacoplan as compared toeculizumab in patients with PNH.66 Overall, 80 patients with PNH, aged ⩾ 18 years andhemoglobin < 10.5 g/dl despite ⩾ 3 months of eculizumab treatment,completed a 4-week run-in period with pegcetacoplan plus eculizumab before1:1 randomization (stratified by the number of packed RBC transfusions in12 months prior to screening [<4 or ⩾ 4] and platelet count [<100,000or ⩾ 100,000 cells × 109/L] at screening) to monotherapy withpegcetacoplan (n = 41) or eculizumab(n = 39) for 16 weeks.66,75

To reduce the burden of daily dosing on patients and to promote compliance, atwice weekly dosing regimen of 1080 mg via subcutaneous infusion wasselected for the phase III trial based on preliminary pharmacokinetic dataand modeling.13,64 Data from the PEGASUS trial demonstrated thatpatients with PNH reached steady-state serum concentrations of pegcetacoplan(655–706 µg/mL) approximately 4–6 weeks following the first dose.13,66

At Week 16, pegcetacoplan was superior to eculizumab for the primary endpointof change in hemoglobin level from baseline, with an adjusted (leastsquares) mean difference of 3.84 g/dL (p < 0.0001;Table 1).66 Pegcetacoplan was also superior to eculizumab at Week 16 for thesecondary endpoint of hemoglobin normalization (defined as hemoglobinlevel ⩾ the LLN range) in the absence of transfusions, while non-inferioritywas shown for secondary endpoints of freedom from transfusions (also knownas transfusion avoidance) and ARC, but not for LDH.66 Clinically meaningful improvements of ⩾ 3-points35 in FACIT-Fatigue score were seen in patients receiving pegcetacoplan,but not eculizumab (Table 1).66 be Additional subgroup analyses according to pre-trial transfusionrequirements revealed that improvements in hemoglobin levels from baselinewere similar among pegcetacoplan-treated patients who received < 4 or ⩾ 4transfusions in the 12 months before screening (<4: 2.97 g/dL and ⩾ 4: 2.11 g/dL).66 In contrast, eculizumab-treated patients who received < 4transfusions in the 12 months before screening only had a hemoglobin leveldecrease of 0.001 g/dL compared to 4.02 g/dL in the ⩾ 4 transfusions group.66 These data demonstrate that even patients who have a high transfusionrequirement before the trial can benefit from pegcetacoplan treatment. Inaddition, although 27% of the patients randomized to the pegcetacoplan armhad a history of bone marrow failure with aplastic anemia, the inclusion ofthese patients in the study had no apparent negative effects on the efficacyresults for pegcetacoplan.

Categorization of hematologic response to treatment, per criteria defined byRisitanoet al. in 2019,59 revealed that 7% of patients in the pegcetacoplan arm and 3% ofpatients in the eculizumab arm exhibited a good, major, or completehematologic response at baseline.71 At Week 16, 73% of patients receiving pegcetacoplan and 5% ofpatients receiving eculizumab exhibited this response (p < 0.0001).71 Patients in the pegcetacoplan arm showed an improved mean score onall EORTC QLQ-C30 functional scales and the global health status/QoL measureat Week 16, while patients in the eculizumab arm showed a mean decrease from baseline.76 Significant improvements in fatigue and dyspnea symptoms were alsoobserved for pegcetacoplan-treated versus eculizumab-treated patients asmeasured by the EORTC QLQ-C30.76

The safety profile of pegcetacoplan was comparable to that of eculizumab.66 The most common TEAEs for patients receiving pegcetacoplan wereinjection site reactions (36.6%) and diarrhea (22.0%;Table 2).66 No cases of meningitis or thrombosis were reported (Table 2).66 Three patients in the pegcetacoplan arm discontinued the trial beforeWeek 16 due to investigator-reported breakthrough hemolysis.66

Overall, pegcetacoplan demonstrated superiority to eculizumab for the primaryendpoint during the 16-week randomized controlled period and was associatedwith improved clinical outcomes in patients with PNH.

Forty-eight-week endpoint: 32-Week open-label period

All 77 patients who completed the PEGASUS 16-week randomized controlledperiod entered the 32-week open-label period as part of apegcetacoplan-to-pegcetacoplan (n = 38) oreculizumab-to-pegcetacoplan (n = 39) arm.72 Pegcetacoplan-to-pegcetacoplan patients completed 32 weeks ofpegcetacoplan monotherapy, while eculizumab-to-pegcetacoplan patientscompleted a 4-week run-in period of dual therapy with eculizumab withpegcetacoplan before switching to pegcetacoplan monotherapy for 28 weeks.72

Pegcetacoplan-to-pegcetacoplan patients maintained comparably high meanhemoglobin levels between Week 16 and Week 48 (p = 0.140),while eculizumab-to-pegcetacoplan patients demonstrated significantly highermean hemoglobin levels at Week 48 as compared with Week 16(p < 0.0001;Table 1).72 Over 70% of all patients in the trial were transfusion-free at Week48 (Table 1).Improvements in ARC, LDH level, and FACIT-Fatigue score (i.e. a clinicallymeaningful improvement of ⩾ 3-points)35 were maintained in the pegcetacoplan-to-pegcetacoplan arm andobserved in the eculizumab-to-pegcetacoplan arm from Week 16 to Week 48(Table 1).72 Categorization of hematologic response to treatment at Week 48, percriteria defined by Risitanoet al.,59 revealed that 63% of patients in the pegcetacoplan-to-pegcetacoplanarm (p = 0.4142 versus 73% at Week 16) and 54% of patientsin the eculizumab-to-pegcetacoplan arm (p < 0.0001versus 5% at Week 16) achieved a good, major, or complete hematologic response.77 At Week 48, patients in both arms showed improvements in QoL, asevidenced by an increased score from baseline on all EORTC QLQ-C30functional scales and the global health status/QoL measure.78 Improvements in fatigue and dyspnea were also observed in both groupsat Week 48 as indicated by EORTC QLQ-C30 symptom scores and were closer tothe population norms.78

There was no significant change in safety profile with pegcetacoplan dosingup to 48 weeks of treatment.72 The most common TEAEs for all patients who received pegcetacoplanwere injection site reactions (26.0%) and hemolysis (19.5%).72 Injection site reactions decreased in frequency as the trialprogressed, suggesting that these events may be less likely as patients gainexperience with subcutaneous self-administration of pegcetacoplan.79 No cases of meningitis were reported throughout the trial (Table 2).72 Thirteen patients, however, discontinued the trial prior to Week 48due to a TEAE, including six discontinuations due to investigator-reportedbreakthrough hemolysis.72

Overall, results of the PEGASUS trial demonstrated that in patients with PNHand suboptimal response to prior eculizumab treatment, pegcetacoplantreatment for up to 48 weeks is durably effective and well-tolerated.

PRINCE

PRINCE (NCT04085601) was a phase III, multicenter, randomized, open-label,controlled trial evaluating the efficacy and safety of pegcetacoplan comparedwith control treatment (supportive care, including blood transfusions,anti-coagulants, corticosteroids, and supplements [iron, folate, and vitaminB12]) in complement-inhibitor-naïve patients with PNH.73,80 A total of 53 patientsaged ⩾ 18 years with hemoglobin levels below the LLN (males: ⩽ 13.6 g/dl;females: ⩽ 12.0 g/dl), LDH levels ⩾ 1.5 times the ULN (1.5 × ULN; ⩾ 339 U/L),and a history of being complement-inhibitor-naïve (i.e. no treatment witheculizumab or ravulizumab within the 3 months before screening) were enrolled inthe trial.80 Patients were randomized 2:1 to receive pegcetacoplan (1080 mgsubcutaneously twice weekly [n = 35]) or control treatment(n = 18) through Week 26.73

Pegcetacoplan was superior to control treatment in both co-primary endpoints ofhemoglobin stabilization (i.e. avoidance of a > 1 g/dL decrease in hemoglobinlevel in the absence of blood transfusions) and change in LDH level frombaseline to Week 26.73 Hemoglobin stabilization was achieved by 85.7% (n = 30)of patients treated with pegcetacoplan and 0.0% of control arm patients throughWeek 26 (p < 0.0001). Pegcetacoplan-treated patientsdemonstrated superior reductions in mean LDH levels from baseline to Week 26compared to control arm patients (least-squares mean change from baseline:pegcetacoplan, −1870.5 U/L; control, −400.1 U/L;p < 0.0001). Pegcetacoplan was also superior to controltreatment for secondary endpoints, change from baseline in hemoglobin levels andtransfusion avoidance. Larger mean hemoglobin level increases were observed inthe pegcetacoplan group versus the control group, and 91.4% ofpegcetacoplan-treated patients versus 5.6% of patients who received controltreatment achieved transfusion avoidance.73

Serious AEs were reported by 8.7% (n = 4) ofpegcetacoplan-treated patients and 16.7% (n = 3) of control armpatients through Week 26 (Table 2).73 Two deaths deemed unrelated to treatment occurred (pegcetacoplan, 2.9%,n = 1, septic shock related to medullary aplasia; control,5.6%,n = 1, respiratory failure).73 The most common TEAEs reported during the trial were injection sitereactions (pegcetacoplan, 30.4%,n = 14; control, 0.0%;Table 2), hypokalemia(pegcetacoplan, 13.0%,n = 6; control, 11.1%,n = 2), and fever (pegcetacoplan, 8.7%,n = 4; control, 0.0%).73 No cases of meningitis or thrombosis were reported in either group (Table 2) and no TEAEsled to discontinuation of pegcetacoplan.73

Patients with PNH who were naïve to complement-inhibitor treatment demonstratedmeaningful hematological and clinical improvements following 26 weeks ofpegcetacoplan treatment in PRINCE. The pegcetacoplan safety profile was similarto previous trials. These results provide evidence for the safety and efficacyof pegcetacoplan treatment in complement-inhibitor-naïve patients with PNH.

Conclusion and future directions

Results from phase I–III clinical trials suggest that pegcetacoplan is efficaciousand safe in a broad population of patients with PNH. This has been demonstratedamong patients with suboptimal response to prior C5i therapy who achieved superiorhemoglobin level improvements with pegcetacoplan compared to eculizumab. Inaddition, superior hematologic improvements were also achieved with pegcetacoplanversus standard treatment (excluding complement-inhibitors) incomplement-inhibitor-naïve patients.

Pegcetacoplan presented a favorable safety profile with injection site reactionsbeing the most common TEAE. As expected, rates of injection site reactions decreasedas the trials progressed. This finding was consistent with the assumption that theseevents would become less common as patients gained experience with pegcetacoplanself-administration and were not a barrier to treatment,79 as numerous QoL gains were reported by patients. No meningococcal infections,a potential concern with complement inhibition, have been observed during clinicalstudies with pegcetacoplan, indicating that mitigation plans to prevent theseinfections (i.e. vaccination strategy and prophylactic antibiotic treatment) areeffective.66,72,73

Pegcetacoplan therapy for patients with PNH has been shown to have several benefitscompared to treatment with other US FDA-approved therapies. In contrast to therequirement for intravenous dosing of eculizumab and ravulizumab, pegcetacoplan canbe self-administered at home by the patient or a caregiver at their convenience(under guidance/training from a healthcare professional); thus eliminating thecontinuous need for an appointed nurse trained in intravenous drug administrationand regular infusion clinic visits.8,9,81 In addition to improvedhematologic parameters, patients receiving pegcetacoplan have reported increased QoLmeasures (such as decreased fatigue levels) in various clinical trials of thedrug.66,76,78 A recent cost analysis demonstrated $1.7 million in costsavings for one US health insurance payer over a 3-year period due to reducedtransfusion requirements and fewer breakthrough hemolysis events when patients weretreated with pegcetacoplan.82

In May 2021, pegcetacoplan (Empaveli) became the first C3-targeted PNH therapy to beapproved by the US FDA for the treatment of adults with PNH, including those whohave switched from treatment with C5i therapies eculizumab and ravulizumab.13 Shortly after, pegcetacoplan was approved for adults with PNH who remainanemic despite stable C5i therapy for at least 3 months by the EMA in December 2021 (Aspaveli),14 and by the Australian Therapeutic Goods Agency in February 2022 (Empaveli;also approved for patients intolerant to C5i therapy).15 Pegcetacoplan’s official label dosing regimen is 1080 mg/20 ml injectionvolume twice weekly, administered as a subcutaneous infusion through an infusionpump (with a reservoir of at least 20 ml).13 For patients switching from C5i therapy, pegcetacoplan should be administeredconcomitantly with the preexisting therapy for 4 weeks, after which the C5i is discontinued.13 Due to complement-inhibitor usage carrying a risk of infection byencapsulated bacteria, the United States prescribing information carries a boxedwarning for infections withNeisseria meningitidis types A, C, W, Yand B,Streptococcus pneumoniae, andHaemophilusinfluenzae type B.13 Recommended mitigation plans to prevent infections with encapsulated bacteriainclude vaccinations againstS. pneumoniae,N.meningitidis, andH. influenzae type B at least2 weeks prior to receiving pegcetacoplan, and antibacterial drug prophylaxis if anunvaccinated patient must receive pegcetacoplan immediately.13

Future investigations with pegcetacoplan for the treatment of PNH should be conductedto further clarify the risk of breakthrough hemolysis with pegcetacoplan, the drug’simmunogenicity, and the long-term risk of encapsulated bacterial infection. Althoughincidences of breakthrough hemolysis were reported by investigators during thePEGASUS trial,66,72 data for breakthrough hemolysis are not available usingpreviously defined criteria (at least one new or worsening symptom/sign ofintravascular hemolysis in the presence of elevated LDH levels after prior LDH levelreduction while on therapy).8,9In addition, treatment with therapeutic peptides is associated with a concern fordrug immunogenicity, and although the immunogenicity of pegcetacoplan has beenevaluated and no apparent negative effects on the safety and efficacy ofpegcetacoplan have been observed, the available methodology and data regarding theformation of antidrug antibodies have not been adequate to fully evaluate theimmunogenicity of pegcetacoplan.13 Furthermore, real-world surveillance of encapsulated bacterial infectionswith pegcetacoplan is needed to fully understand the long-term risk of theseinfections with the drug and C3 inhibition. Of note, an extension study(NTC03531255) to investigate the long-term efficacy and safety of pegcetacoplan83 and a phase II study (NTC04901936) investigating the efficacy and safety ofpegcetacoplan in children with PNH are currently ongoing.84

Pegcetacoplan is also being investigated for the treatment of othercomplement-mediated conditions, including age-related macular degeneration (AMD),geographic atrophy (GA), C3 glomerulopathy, and cold agglutinin disease. Treatmentwith pegcetacoplan has been shown to significantly reduce the growth rate of GAlesions in adults with GA secondary to AMD in the phase II FILLY trial (NTC02503332)85 and the phase III OAKS trial (NCT03525613).86,87 In addition, althoughpegcetacoplan-treated patients with GA secondary to AMD in the phase III DERBY trial(NCT03525600) narrowly missed the primary endpoint of reduction in GA lesions atMonth 12 of the study,86 longer-term analysis of patients has demonstrated that pegcetacoplancontributed to nominally significant reductions in GA lesion growth at Month 18.87 Pegcetacoplan was also associated with a 73.3% reduction in proteinuria infive patients with C3 glomerulopathy in the phase II DISCOVERY trial (NCT03453619)88 and demonstrated preliminary efficacy in patients with cold agglutinindisease in the PLAUDIT trial (NCT03226678).89 It is likely that pegcetacoplan’s approved usage will be expanded to some ofthese conditions in the future, although the dosage and route of administrationremains to be determined.

Increasing interest in the field of complement therapeutics has prompted theexecution of numerous preclinical and clinical trials using novelcomplement-inhibitors and agents.59 As new complement-targeting therapies are approved, the efficacy of thesenovel therapeutics as both primary and combinational therapy options should beinvestigated. Most of the novel therapies in development are proximalcomplement-inhibitors representing three strategic target categories: anti-C3agents, anti-factor D agents, and anti-factor B agents.59 Factor D and factor B are complement mediators within the alternativecomplement pathway, one of the three pathways capable of initiating the processesthat result in C3 activation.90 Proximal complement-inhibitors within these categories are currently underinvestigation for oral or subcutaneous administration for patients with PNH asmonotherapy or in association with C5i therapy.59 Ultimately, pegcetacoplan has demonstrated clinically compelling evidence forthe efficacy and safety of proximal complement inhibition in patients with PNH.Thus, pegcetacoplan together with the development of other novel therapeuticsprovide hope for the future of effective treatment options for the optimalmanagement of PNH and other complement-mediated diseases.

Acknowledgments

The author thanks Francie Moehring, PhD, Nicole Green, MD, and Apeksha Shenoy, MSE ofBoston Strategic Partners, Boston, MA, USA for their medical writing support,editorial support, and assistance with article submission on the author’s behalf(funded by Apellis Pharmaceuticals, Inc). The author approves of the article’scontent, accuracy, and integrity per ICMJE criteria, and all statements anddeclarations contained therein. Apellis Pharmaceuticals, Inc and Swedish OrphanBiovitrum AB reviewed the article.

Footnotes

ORCID iD: Raymond S.M. WongInline graphichttps://orcid.org/0000-0002-9011-4268

Declarations

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Author contribution(s):Raymond S.M. Wong: Conceptualization; Writing – original draft;Writing – review & editing.

Funding: The author disclosed receipt of the following financial support for theresearch, authorship, and/or publication of this article: This work wassupported by Apellis Pharmaceuticals, Inc.

Competing interests: The author declared the following potential conflicts of interest withrespect to the research, authorship, and/or publication of this article:Raymond S.M. Wong: Alexion Consultancy, Honoraria, Research Funding andSpeakers Bureau, Apellis Research Funding and Speakers Bureau, RocheConsultancy, Honoraria, Research Funding and Speakers Bureau

Availability of data and materials: Not applicable.

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