FormalPara Key Summary Points

Why carry out this study?

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematologic disease for which complement component 5 (C5) inhibitor standard-of-care treatments provide inadequate disease control in some patients and require regular clinic visits for intravenous treatment administration

Pegcetacoplan is approved by the United States Food and Drug Administration for the treatment of adults with PNH and by the European Medicines Agency for the treatment of adults with PNH plus anemia despite receiving C5-targeted therapy for ≥ 3 months. Pegcetacoplan demonstrated durable clinical benefit and a favorable safety profile in the phase 3 PEGASUS trial (NCT03500549). Patients with PNH receiving pegcetacoplan via self-administered subcutaneous (SC) injections in PEGASUS who experienced injection site reactions (ISRs) experienced mild ones. To better understand the long-term tolerance of pegcetacoplan SC injections, the incidence and severity of ISRs with an additional 48 weeks of pegcetacoplan treatment in the PEGASUS cohort of the open-label extension (OLE) of Study 307 (307 OLE; NCT03531255) were investigated

What was learned from this study?

With longer-term pegcetacoplan treatment in the PEGASUS cohort of the 307 OLE, most patients reported ISRs with a maximum severity of mild, consistent with the observations in PEGASUS. The percentage of patients reporting ISRs declined from PEGASUS through the 307 OLE, and compliance remained high, suggesting that ISRs are not a barrier to continued pegcetacoplan treatment in patients with PNH

Patient education about proper self-administration techniques may help mitigate the impact of ISRs on the patient experience and enable patients to continue to obtain long-term disease control with pegcetacoplan treatment

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by continuous complement activation leading to hemolysis, chronic symptoms of anemia, fatigue, and hemoglobinuria, and life-threatening thrombosis [1]. Complement inhibition is the standard-of-care approach for PNH treatment [2,3,4]. However, some currently available therapies, such as the complement component 5 (C5) inhibitors eculizumab and ravulizumab, do not provide comprehensive disease control in some patients because of C3-mediated extravascular hemolysis and require regular clinic visits for administration via intravenous (IV) infusion by a healthcare professional.

Pegcetacoplan is a pegylated pentadecapeptide approved in the US for the treatment of adults with PNH and in the EU for adults with PNH and anemia despite receiving C5-targeted therapy for ≥ 3 months [5,6,7]. Pegcetacoplan binds to complement component C3 and its activation fragment C3b, thereby regulating downstream effectors of complement activation [8]. In the phase 3 PEGASUS trial (NCT03500549), pegcetacoplan was found to be superior to eculizumab in improving clinical and hematologic outcomes in patients with PNH previously treated with eculizumab and had a favorable safety profile with up to 48 weeks of treatment [7, 9]. The long-term safety and efficacy of pegcetacoplan in patients with PNH from PEGASUS and other phase 1–3 pegcetacoplan clinical trials is being evaluated in the Study 307 open-label extension (307 OLE; NCT03531255) [10].

Pegcetacoplan is administered as a one or two bolus subcutaneous (SC) injection over 30–60 min with an ambulatory syringe pump by patients or their caregivers at home after receiving training from a healthcare provider [5,6,7]. Self-administered SC treatments may reduce treatment burden and therefore may have an advantage over IV therapies in patients with PNH [11]. Injection site reactions (ISRs) are frequently reported with subcutaneously injected drugs; they are defined as specific local skin reactions originating around the injection site and manifesting as erythema, induration, itching, discomfort, and pain, or, more severely, as ulceration or necrosis [12, 13]. ISRs were a common but mostly mild, treatment-emergent adverse event (TEAE) observed with pegcetacoplan SC self-administration in PEGASUS [7, 9]. They are also commonly observed (0.5–40%) in patients receiving SC treatments for multiple chronic diseases, including PNH, and may lead to the unnecessary discontinuation of treatment [13, 14]. Considering that ISRs are common with any subcutaneously delivered drug [15], pegcetacoplan-associated ISRs are no different from those observed with other SC-administered treatments.

Given that SC injections are a newer route of administration for PNH treatments [16], data are limited on the frequency and impact of ISRs in patients with PNH who will chronically self-administer these treatments. In this analysis, we aim to determine the incidence and severity of ISRs associated with long-term pegcetacoplan treatment, utilizing data from patients in PEGASUS and the PEGASUS cohort of the 307 OLE.

Methods

Study Design and Patients

Full study design details and patient inclusion/exclusion criteria for PEGASUS have been previously reported [7, 9]. In brief, PEGASUS was a multi-center, open-label, randomized, active comparator-controlled, phase 3 trial that evaluated pegcetacoplan compared with eculizumab [7, 9]. Eligible patients were adults (≥ 18 years of age) with PNH diagnosed by high-sensitivity flow cytometry with a hemoglobin concentration of < 10.50 g/dl after ≥ 3 months of stable eculizumab treatment. Enrolled patients received pegcetacoplan + eculizumab during a 4-week run-in period, followed by a 16-week randomized controlled period (RCP) during which patients were randomized 1:1 to receive pegcetacoplan monotherapy twice per week or eculizumab monotherapy. During the 16-week RCP, patients randomized to eculizumab received a dosing regimen in accordance with their regimen at enrollment (900–1500 mg IV twice per week [n = 79]; 900 mg IV every 11 days [n = 1]). The RCP was followed by a pre-specified 32-week open-label period (OLP) during which all patients receiving pegcetacoplan continued with treatment (pegcetacoplan-to-pegcetacoplan) and patients receiving eculizumab switched to pegcetacoplan (eculizumab-to-pegcetacoplan). During the OLP, patients in the eculizumab-to-pegcetacoplan group received pegcetacoplan + eculizumab for weeks 17–20 and then continued with pegcetacoplan monotherapy until week 48. Pegcetacoplan was self-administered twice per week or every 3 days using either two 10-ml SC injections of approximately 30 min each at two distinct sites or one 20-ml injection of approximately 60 min at one injection site (20 ml total of 1080 mg/20 ml solution). Dosing every 3 days was permitted at the first instance of lactate dehydrogenase (LDH) levels > two times the upper limit of normal (ULN).

The 307 OLE is an ongoing, open-label extension study that enrolled adults with PNH who completed previous phase 1 (PHAROAH and PADDOCK), phase 2 (PALOMINO), and phase 3 (PEGASUS and PRINCE) pegcetacoplan trials [10]. Patients from PEGASUS who enrolled in the 307 OLE continued to receive pegcetacoplan 1080 mg SC twice or every 3 days. Patients receiving 1080 mg SC every 3 days could increase dosing to three times weekly if LDH > two times ULN occurred on only one occasion.

PEGASUS and the 307 OLE were conducted in accordance with guidance for Good Clinical Practice and the Declaration of Helsinki [7, 9]. Clinical trial protocols were approved by the Institutional Review Boards/Ethics Committees at each participating trial site (see Table S1 in the electronic supplementary materials). All patients provided written informed consent before enrollment in both PEGASUS and the 307 OLE.

Safety Analysis

Safety was assessed in the PEGASUS and the 307 OLE Safety Populations (including all randomized patients who received at least one dose of pegcetacoplan) [7]. Safety endpoints included the incidence and severity of AEs and TEAEs, including ISRs. TEAEs were defined as AEs occurring or worsening in severity during treatment and within 30 days after the last dose [7]. Relatedness of a TEAE to pegcetacoplan was determined by the investigator. In both trials, data were summarized by System Organ Class (SOC) and Preferred Term (PT) in accordance with Medical Dictionary for Regulatory Activities (MedDRA) version 23.0.

On-site data monitoring for the trials was performed by the sponsor’s designee for the duration of the study [7]. The monitor verified the accuracy and completeness of the electronic case report form entries, source documents, and other study-related records.

Injection Training and ISR Collection

Pegcetacoplan was administered as SC injections by trained research personnel at the PEGASUS baseline visit [7]. Patients then transitioned to self-administered SC injections at home using an ambulatory syringe pump. The preferred site of injection was the abdomen; however, if a patient did not tolerate administration into the abdomen, alternative sites could be selected (e.g., thigh or upper arm). On the days of clinical visits, pump safety assessments, during which patients were asked about issues related to pump use, were performed by a physician or other licensed healthcare provider within 30 min of study drug administration. Self-administration conducted at the clinic was supervised to ensure patient compliance with administration guidelines.

Patients were instructed to notify the investigator or other study personnel of ISRs or any potential issues with pump use during self-administration [7]. All clinically relevant events of ISRs or potential pump-related issues, as determined by the investigator, were recorded as AEs. Injection site assessments were performed throughout PEGASUS as described [7, 9] and in the 307 OLE during clinical visits at baseline, week 2 (only for patients switching doses or regimens), week 4, and then every 12 weeks until the exit visit 8 weeks after the final dose. A subset of MedDRA terms were defined in this analysis as constituting an ISR (Table S2). [17, 18]

Data Analysis

This analysis included patients who completed PEGASUS (the phase 3 parent trial with the longest duration of follow-up) and subsequently enrolled in the 307 OLE (n = 64) [9, 19]. No formal statistical analyses of TEAEs were performed. Continuous data were summarized using descriptive statistics (i.e., n, mean, median, standard deviation [SD], minimum, maximum), and categorical data were summarized by the number of patients and the percentage of patients in each category. The data cut-off date for this interim analysis of the 307 OLE was August 27, 2021.

Results

Patients

In PEGASUS, 80 patients were randomized to receive pegcetacoplan (n = 41) or eculizumab (n = 39) and entered the run-in period and the RCP [7, 9]. The majority of patients (92.7% pegcetacoplan and 100% eculizumab) completed the RCP and entered the OLP, during which all patients remained on pegcetacoplan (pegcetacoplan-to-pegcetacoplan) or switched to pegcetacoplan (eculizumab-to-pegcetacoplan). Sixty-seven patients (32 in pegcetacoplan-to-pegcetacoplan arm and 35 in eculizumab-to-pegcetacoplan arm) completed 48 weeks of treatment, and 64 patients (32 in pegcetacoplan-to-pegcetacoplan arm and 32 in eculizumab-to-pegcetacoplan arm) entered the 307 OLE [9, 10]. As of the data cutoff date for this analysis, 58 patients from PEGASUS completed 48 weeks of additional treatment in the 307 OLE.

Three patients in the pegcetacoplan arm of the PEGASUS RCP discontinued due to TEAEs [7, 9]. In the PEGASUS OLP, two patients in the pegcetacoplan-to-pegcetacoplan arm and seven patients in the eculizumab-to-pegcetacoplan arm discontinued due to TEAEs. One additional patient in the pegcetacoplan-to-pegcetacoplan arm discontinued the OLP due to a physician’s decision. As of this analysis, six patients from the PEGASUS cohort withdrew from the 307 OLE due to AEs (n = 3), physician decision (n = 2), or loss to follow-up (n = 1).

The median duration of pegcetacoplan treatment in PEGASUS was 223.5 (range 33–440) days and included 5960 completed injections. In the PEGASUS cohort of the 307 OLE, the median duration of treatment was an additional 337.0 (range 55–344) days and included an additional 5972 completed injections. Compliance rates of ≥ 80% and ≤ 120% were observed in 98.8% (79 of 80) and 95.3% (61 of 64) of patients in PEGASUS and the PEGASUS cohort of the 307 OLE, respectively.

Patient demographics and baseline disease characteristics for patients from PEGASUS have been previously published [7, 9]. In the PEGASUS cohort of the 307 OLE, the mean age was 48.5 (SD 15.2) years, 60.9% were women, and 62.5% were white (Table 1). Baseline hemoglobin levels in the PEGASUS cohort of the 307 OLE (mean 11.5 [SD 1.8] g/dl) were higher than baseline levels observed before pegcetacoplan treatment in the pegcetacoplan (mean 8.7 [SD 1.1] g/dl) or eculizumab (mean 8.7 [0.9] g/dl) arms of PEGASUS. [7, 9]

Table 1 Demographics and disease characteristics at PEGASUS entry for patients with PNH who had completed the PEGASUS trial and enrolled in the 307 OLE
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ISRs

In PEGASUS and the 307 OLE, the percentage of patients experiencing ISRs declined with longer-term treatment [7, 9]. During the run-in period, 47 patients (58.8%) in the pegcetacoplan + eculizumab group experienced an ISR (Table 2). The percentage of patients experiencing ISRs declined in the RCP (pegcetacoplan group 36.6%) and the OLP (combined pegcetacoplan-to-pegcetacoplan and eculizumab-to-pegcetacoplan groups 26.0%). At 48 weeks of treatment in the 307 OLE, ISRs were reported in 14.1% (9 of 64) of patients in the PEGASUS cohort.

Table 2 Summary of patients with ISRs in PEGASUS and the PEGASUS cohort of the 307 OLE
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The majority of patients in PEGASUS with ISRs experienced events with a maximum severity of mild during the run-in period (44 of 47 patients [93.6%]), the RCP (pegcetacoplan group 14 of 15 patients [93.3%], eculizumab group 1 of 1 patient [100%]), and the OLP (combined pegcetacoplan-to-pegcetacoplan and eculizumab-to-pegcetacoplan groups 18 of 20 patients [90.0%]) (Table 2) [7, 9]. ISRs with a maximum severity of moderate reported in PEGASUS included ISR (n = 1 in the run-in period), infusion site reaction (n = 1 in the run-in period), injection site pruritus (n = 2 in the run-in period and n = 1 in the OLP), injection site pain (n = 1 in the run-in period and n = 1 in the OLP), and infusion site urticaria (n = 1 in pegcetacoplan arm of the RCP). In the 307 OLE, consistent with PEGASUS, patients with ISRs had mostly mild events (7 of 9 patients [77.8%]). Two patients in the 307 OLE experienced ISRs with a maximum severity of moderate (1 event each of ISR and injection site scar). None of the ISRs in PEGASUS or the PEGASUS cohort of the 307 OLE were classified as severe or serious TEAEs or led to drug discontinuation.

Injection site erythema was the most common ISR type observed in patients who received pegcetacoplan with or without eculizumab in the PEGASUS run-in period, the RCP, and the OLP (Table 2). In the run-in period, this was followed by injection site pruritus, swelling, reaction, pain, induration, and bruising. In the PEGASUS cohort of the 307 OLE, injection site erythema and induration were the most common ISRs (6.3% [4 of 64 patients] each). In general, the percentage of patients reporting specific ISR events declined from the PEGASUS run-in period through the RCP and the OLP and into the 307 OLE.

The pegcetacoplan-related ISRs that were most common during the PEGASUS run-in period and the RCP were injection site erythema, swelling, pruritus, reaction, induration, and pain (Table 3). In the PEGASUS cohort of the 307 OLE, injection site erythema and induration were the most common pegcetacoplan-related ISRs (4.7% [3 of 64 patients] each).

Table 3 Summary of patients with ISRs related to pegcetacoplan in PEGASUS and the PEGASUS cohort of the 307 OLEa
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The exposure-adjusted rates of injection site erythema (the most common ISR) are 56.8 per 100 patient-years in the pegcetacoplan group of the PEGASUS RCP and 20.1 per 100 patient-years in the combined eculizumab-to-pegcetacoplan and pegcetacoplan-to-pegcetacoplan groups of the PEGASUS OLP (Table 4). In the 307 OLE, the exposure-adjusted rates of injection site erythema and induration (the most common ISRs) were 6.5 per 100 patient-years each over 48 weeks. In general, the exposure-adjusted rate of specific ISR events declined from the PEGASUS run-in period through the RCP and the OLP.

Table 4 Exposure-adjusted incidence of ISRs in PEGASUS and the PEGASUS cohort of the 307 OLE
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Discussion

Prior to the introduction of complement inhibitors, treatments for PNH were generally supportive, with allogeneic hematopoietic stem cell transplantation (allo-HCT) representing the only option targeting the underlying PNH disease pathology [20, 21]. However, given the risks of transplant-related morbidity and mortality, the use of allo-HCT is limited to patients who are refractory to C5 inhibitors (eculizumab or ravulizumab) [21]. Despite improvements in clinical PNH manifestations observed with long-term C5 inhibitor treatment, many patients continue to experience a substantial burden of illness and need additional therapeutic options [2, 22, 23]. In the phase 3 PEGASUS trial, treatment with pegcetacoplan, the first targeted C3 therapy, induced durable hematologic and clinical responses in patients with PNH who had an inadequate response to standard-of-care treatment with a C5 inhibitor [7, 9]. As previously reported, ISRs were common, but mainly mild in severity, with up to 48 weeks of pegcetacoplan SC self-administration in PEGASUS [7, 9]. In this long-term analysis, which captures more than 1.5 years of pegcetacoplan treatment and more than 11,900 completed injections in the PEGASUS study and the PEGASUS cohort of the 307 OLE, the maximum severity of ISRs experienced by most patients with ISRs was mild. The percentage of patients reporting ISRs declined from PEGASUS to the 307 OLE, which we postulate may be attributed to increased patient experience with SC injections and mitigation strategies. There were no severe or serious ISRs or ISRs that led to treatment discontinuation in either PEGASUS or the 307 OLE. The most common ISR events (e.g., injection site erythema and induration) were consistent between PEGASUS and the 307 OLE. These data, coupled with the high treatment compliance rate observed in this analysis (i.e., > 95% in both studies) and previously reported [24] clinically meaningful improvements in overall health-related quality of life in PEGASUS, suggest that ISRs are not a barrier to continued pegcetacoplan treatment in patients with PNH.

In studies of ravulizumab, ISRs were common with long-term administration using the IV formulation (approved in the US and EU) and the SC formulation delivered using an on-body delivery system (approved in the US) [14, 25, 26]. In a 1-year analysis of the ravulizumab phase 3 Study 303 (NCT03748823), ISR and injection site erythema occurred in 6.0% and 4.8% of patients, respectively. [14] Medical device site erythemas, including reactions related to device attachment to the skin, were reported in 3.6% of patients. The rates of infusion reactions, including local, systemic, and immune-mediated reactions, were 45.2% with up to 71 days of treatment and 54.8% with up to 351 days of treatment. The incidence of local ISRs only has not been reported. The most common AEs unrelated to a device product issue with ravulizumab SC were ISR (4.7%), medical device site erythema (3.9%), and infusion/injection site erythema (3.1%). One patient experienced two serious events of application site induration and procedural hypotension during ravulizumab SC administration. Similar to the long-term pegcetacoplan data presented here, the incidence of infusion site reactions with ravulizumab treatment decreased over time (0–6 months: 197.4 events/100 patient-years; > 6–12 months: 13.2 events/100 patient-years), and compliance rates remained high (99.9%). Clinical development is still in the early stages for other PNH therapies targeting C3, C5, or other disease targets administered as a SC injection [16]. Longer-term follow-up with other therapies in development for PNH will help determine the impact of ISRs within the overall treatment landscape.

Subcutaneous injection offers many advantages over the IV route, including lower cost and requirements for less skilled personnel [27,28,29]. Patients who participated in PEGASUS received pegcetacoplan self-injection training from a healthcare professional at the start of the study [7], which may have led to the high compliance rate observed. A convenient, wearable, single-use, automatic injector device with a hidden needle has been developed for pegcetacoplan administration into the abdominal area [30]. In a human factors usability study, this wearable injector device was shown to be safe and effective when utilized by adults with anemia and caregivers following a training session on the injector and a review of the instructions for use. The new device, when coupled with patient education, is expected to improve the patient experience with self-injections.

In PEGASUS and the 307 OLE, the preferred site of injection was the abdomen; however, patients were allowed to alternate injection site locations to other areas, such as the thigh or upper arm [7]. Abdominal SC injection was reported to be less painful than injection into the thigh with other SC drugs [31], but the rotation of the injection site location can be helpful to minimize ISRs overall [15]. Furthermore, the pegcetacoplan injection pump instructions for use recommend rotating injection site locations and avoiding skin that is tender, bruised, red, or hard, or skin that has scars, tattoos, or stretch marks [5].

Pre-treatments to mitigate ISRs, such as the use of skin-cooling interventions or topical numbing or analgesic agents [15], were not included in PEGASUS or the 307 OLE. Therefore, a limitation of this analysis is the lack of data on the impact of these ISR mitigation strategies commonly used in the real-world setting on the incidence and severity of pegcetacoplan-associated ISRs. Furthermore, the small sample size and observational nature of this safety analysis should also be noted as limitations.

Conclusion

Long-term data from the PEGASUS cohort of the 307 OLE demonstrate that pegcetacoplan was generally well tolerated with a favorable safety profile, despite the incidence of ISRs, in patients with PNH. Most ISRs reported by patients were a maximum severity of mild, and ISRs did not cause discontinuations in a clinical trial setting. The percentage of patients reporting ISRs declined with longer treatment, potentially as patients became more experienced with self-injections. The new pegcetacoplan wearable, single-use automatic injector device may improve the patient experience with pegcetacoplan self-injection by helping patients more conveniently manage PNH.