CADTH Reimbursement Review

Pegcetacoplan (Empaveli)

Sponsor: Sobi Canada Inc.

Therapeutic area: Paroxysmal nocturnal hemoglobinuria

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare chronic disease characterized by intravascular hemolysis (IVH) and heterogenous signs and symptoms that include hemoglobinuria, anemia, abdominal pain, dyspnea, fatigue, dysphagia, and erectile dysfunction.¹ Complications of PNH include thrombosis, chronic kidney disease, and pulmonary hypertension.² Although the incidence of PNH has not been extensively characterized, 1 study in the UK estimated an annual incidence of clinical PNH of approximately 0.13 per 100,000 persons.³ PNH is a consequence of an acquired genetic mutation, leading to clonal expansion of hematopoietic stem cells that produce abnormal blood cells that are susceptible to complement-mediated IVH.²

Terminal complement component 5 (C5) inhibitors (e.g., eculizumab, ravulizumab) are the first-line standard of care for patients with hemolytic PNH that has high disease activity (i.e., symptomatic and lactate dehydrogenase [LDH] 1.5 times above the upper limit of normal [ULN], indicative of clinically significant IVH). Approximately 20% to 30% of patients have ongoing and clinically significant anemia, despite C5 inhibitor treatments, due to reasons such as breakthrough IVH, complement component 3 (C3)-mediated extravascular hemolysis (EVH), development of human-antihuman or eculizumab-neutralizing antibodies, and C5 genetic polymorphism.¹ Prior to the approval of pegcetacoplan, there was no approved subsequent therapy for patients with an inadequate response to a C5 inhibitor due to C3-mediated EVH. The clinical experts consulted by CADTH noted that the current treatment approach for these patients is to provide best supportive care (e.g., red blood cell [RBC] transfusion, steroids, splenectomy, danazol, epoetin alfa) while continuing C5 inhibitor treatment, although many best supportive care therapies are associated with toxicities. Referral to clinical trials is an alternative option. Patients with concurrent bone marrow insufficiency may also receive immunosuppressive therapy.

Pegcetacoplan is a proximal C3 inhibitor that has an indication for the treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor. The product monograph recommends pegcetacoplan 1,080 mg subcutaneous infusion be given twice weekly with a syringe system infusion pump by a health care professional, the patient, or a caregiver.⁴ A dosage increase to 1,080 mg every third day may be considered if the LDH level is at least 2 times above the ULN on twice-weekly dosing.⁴ This is the first CADTH reimbursement review for pegcetacoplan.

The objective of this report is to perform a systematic review of the beneficial and harmful effects of pegcetacoplan (54 mg/mL) solution for subcutaneous infusion for the treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

The Canadian Association of PNH Patients and the Aplastic Anemia & Myelodysplasia Association of Canada submitted a joint input for this review. Information was gathered through 1-on-1 interviews with 6 individuals diagnosed with PNH living in Canada and from the scientific literature. The patient group expressed the following negative impacts of PNH: persistent anemia (manifested as fatigue or extreme fatigue), hemolysis leading to thrombosis, employment absenteeism for patients and caregivers, dependence on frequent blood transfusions, and reduced quality of life (QoL). According to the input, patients with PNH, particularly those experiencing EVH, need alternative treatment options because of the inability of available treatments with eculizumab or ravulizumab to thoroughly control IVH and prevent EVH. The patient group also expressed the need for therapies to improve anemia, reduce or eliminate transfusion requirements, and improve fatigue and QoL. Among the 3 patients who had used pegcetacoplan, all noted an immediate normalization of hematological parameters, easier administration (self-administered subcutaneous infusion twice weekly at home) than eculizumab or ravulizumab (requiring visits for IV transfusions), reduced blood transfusions, and improved physical functioning and QoL. Some patients stated the importance for proper injection training.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts noted there is a need for treatments that are effective in patients who have insufficient control of IVH despite treatment with eculizumab, address the issue of C3-mediated EVH, and can be used in patients with intolerance to C5 inhibitors or poor venous access. The clinical experts noted that pegcetacoplan is a C3 inhibitor with a mechanism of action in addition to C5 inhibitors because it inhibits a more upstream effector than C5 in the complement activation pathway. They anticipated that the drug would serve as a second-line treatment for PNH.

The clinical experts noted that suitable candidates for pegcetacoplan treatment include patients with PNH who have persistent anemia (with or without a history of ongoing blood transfusion needs) and evidence of EVH despite an adequate trial of C5 inhibitor treatment, patients with intolerance to a C5 inhibitor, and patients with a rare C5 genetic polymorphism (which prevents eculizumab from binding to its target molecule and is mainly present in patients of Japanese descent). The clinical experts noted that pegcetacoplan could be considered in patients who are geographically isolated or who have poor venous access. Patients with a PNH clone size (i.e., the proportion of blood cells deficient in complement system regulatory protein) of less than 10% should not receive pegcetacoplan.

The clinical experts noted that a clinically meaningful treatment response would include improvements in hemolytic parameters (LDH, bilirubin), hemoglobin (Hb) level, and QoL, and a reduction in transfusion needs. In general, follow-up assessments are conducted every 3 months, and treatment response is determined, per clinical judgment, by the treating physician based on a global assessment of all patient parameters, chronology of symptoms, and laboratory results. The clinical experts noted that treatment discontinuation is not considered unless 1 of the following occurs: treatment failure (persistent anemia and ongoing transfusion needs) necessitating a switch to a more effective treatment, intolerance to pegcetacoplan, or resolution of disease after bone marrow transplant. The clinical experts noted that patients with PNH should be managed by hematologists in consultation with PNH specialists.

Clinician Group Input

One clinician group, the Canadian PNH Network, submitted input for this review based on contributions from 11 clinicians. The group noted that the current standard of care is C5 inhibitors (i.e., eculizumab and ravulizumab), which act via terminal complement blockade. They noted that although C5 inhibitors are not curative treatment, these treatments have been shown to be effective in controlling IVH, leading to significant improvements in fatigue, QoL, transfusion dependence, thrombosis, and overall survival. The only curative treatment for PNH is allogeneic hematopoietic stem cell transplant, which is available to patients with predominant or progressive bone marrow failure or eligible patients with evidence of clonal evolution. However, the group highlighted 3 unmet needs: some patients do not have access to standard care due to highly restrictive reimbursement criteria; eculizumab has a high treatment burden because it requires venous access for administration and nurse visits every 2 weeks; and, despite treatment, approximately one-third of patients remain anemic due to EVH and some are transfusion-dependent. The group expressed that drugs that exploit proximal complement blockade, such as C3 inhibitors, address the EVH risk, significantly increase Hb, and improve QoL. Regarding place in therapy, the group stated pegcetacoplan is the first C3 inhibitor that protects against EVH and noted that it would fit into the current treatment landscape as an alternative (i.e., switch) option for patients with no or inadequate response or intolerance to eculizumab or ravulizumab. These would include patients with persistent anemia (Hb less than 10.5 g/dL or perhaps higher, if symptomatic) despite stable doses of eculizumab or ravulizumab and those who have had other causes of ongoing anemia (e.g., breakthrough hemolysis or bone marrow failure) ruled out. The group indicated that a clinically meaningful response to treatment would be sustained control of LDH level (i.e., below 1.5 times the ULN), an increase in Hb (or possibly Hb stabilization without further need for transfusion), and improvement in anemia-related symptoms. Treatment discontinuation should be considered in patients who have adverse events (AEs) that preclude ongoing therapy (e.g., recurrent breakthrough hemolysis, issues with effective self-administration, intolerable pain from infusion). The group indicated that the treatment and monitoring of patients should ideally be done by clinicians who specialize in the area, although patients can self-administer pegcetacoplan at home or anywhere they prefer.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a CADTH recommendation for pegcetacoplan:

• relevant comparators

• consideration for initiation of therapy

• consideration for continuation or renewal of therapy

• consideration of discontinuation of therapy

• consideration for prescribing of therapy

• generalizability

• care provision issues

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4 for more details.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The CADTH systematic review identified 1 relevant study, PEGASUS,⁵ which was a pivotal phase III, open-label, randomized controlled trial (RCT) comparing pegcetacoplan (1,080 mg twice weekly via subcutaneous infusion) with eculizumab (at a patient’s established dosage regimen via IV infusion) in adult patients with PNH who continued to have Hb levels of less than 10.5 g/dL despite treatment with eculizumab at a stable dosage for at least 3 months (N = 80). After receiving both interventions concurrently in a 4-week run-in period, patients were randomized to either pegcetacoplan or eculizumab monotherapy in a 1:1 ratio for a 16-week randomized controlled period. The primary outcome was change from baseline (before the run-in period) at week 16 in Hb (primary end point), and the key secondary end points were transfusion avoidance, change in baseline at week 16 in absolute reticulocyte count (ARC), LDH, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score.

At baseline, the mean age was 48.8 years (standard deviation [SD] = 16.0 years) and the majority of patients were female and white (both 61.3%). Patients had a mean time since diagnosis of 10.2 years (SD = 8.6 years), had received eculizumab for a mean duration of 1,808.7 days (SD = 1,447.6 days) before the study, and 30% of patients received eculizumab at a dose higher than the maintenance dose approved for PNH by Health Canada. The study population had a mean Hb level of 8.7 g/dL (SD = 1.0 g/dL), reasonable control of IVH (mean LDH = 282.4 U/L; SD = 211.0 U/L), elevated mean ARC (mean = 216.9 × 10⁹ cells/mL; SD = 71.7 × 10⁹ cells/mL) and indirect bilirubin (mean = 33.8 µmol/L; SD = 25.8 µmol/L) levels, and low haptoglobin (mean = 0.135 g/L; SD = 0.121 g/L), all of which were consistent with the signs of EVH.

Efficacy Results

The key efficacy results from the PEGASUS trial are summarized in Table 2.

Table 2: Summary of Key Results From the Pivotal Trial — Randomized Controlled Period

ARC = absolute reticulocyte count; CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy; Hb = hemoglobin; ITT = intention to treat; LDH = lactate dehydrogenase; LS = least square; SD = standard deviation; SE = standard error; TEAE = treatment-emergent adverse event.

^aBaseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

^bThe analysis was conducted using a mixed model for repeated measures (MMRM), with change from baseline at week 16 in outcome measure as the dependent variable. The model was adjusted for treatment group, study visit, number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³), the study visit by treatment group interaction, and baseline measurement level (continuous).

^cThe significance threshold was set at a 2-sided alpha of 0.05.

^dHb response was defined as an increase of at least 1 g/dL in Hb from baseline, excluding data before the randomized controlled period.

^eThe risk difference and 95% CI were constructed using the stratified Miettinen-Nurminen method.

^fHb normalization was defined as a Hb level at or above the lower limit of the normal range.

^gTransfusion avoidance was defined as the proportion of patients who did not require a transfusion during the randomized controlled period. Patients who did not have a transfusion but withdrew before week 16 were considered to have had a transfusion.

^hIn accordance with the hierarchal testing procedure, noninferiority but not superiority testing was conducted.

ⁱThe P value was based on Cochran-Mantel-Haenszel chi-square test stratified by the number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4) and the platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³).

^jIn accordance with the hierarchal testing procedure, neither noninferiority nor superiority testing was conducted.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Survival

Survival was not assessed in the efficacy analysis.

Hb Outcomes

Change from baseline at week 16 in Hb level was the primary end point. The mean Hb level at baseline was 8.69 g/dL (SD = 1.08 g/dL) in the pegcetacoplan arm and 8.68 g/dL (SD = 0.89 g/dL) in the eculizumab arm. The least square (LS) mean change from baseline at week 16 in Hb level (censored for transfusion) was 2.37 g/dL (standard error [SE] = 0.36 g/dL) in the pegcetacoplan arm and –1.47 g/dL (SE = 0.67 g/dL) in the eculizumab arm, with a between-group difference of 3.84 g/dL (95% confidence interval [CI], 2.33 to 5.34 g/dL) in favour of pegcetacoplan (P < 0.0001). Results of the sensitivity analyses (controlled-based pattern imputation and tipping point analyses) and supportive analysis using all patient data (uncensored for transfusion) were consistent with the primary analysis.

Hb response (i.e., at least 1 g/dL increase) in the absence of transfusion (secondary end point) was achieved in 75.6% of patients in the pegcetacoplan arm and 0% of patients in the eculizumab arm, with an adjusted risk difference of 67.5% (95% CI, 54.5% to 80.4%). Hb normalization in the absence of transfusion at week 16 (secondary end point) was achieved in 34.1% of patients in the pegcetacoplan arm and 0% of patients in the eculizumab arm, with an adjusted risk difference of 30.4% (95% CI, 14.9% to 45.9%). The differences between treatments for both outcomes were not tested for statistical significance.

Transfusion

Transfusion avoidance was a key secondary end point and was tested for noninferiority according to the hierarchal testing procedure. Transfusion avoidance was achieved in 85.4% of patients in the pegcetacoplan arm and 15.4% of patients in the eculizumab arm, with an adjusted risk difference of 62.5% (95% CI, 48.3% to 76.8%) in the intention-to-treat (ITT) analysis. The lower bound of the 95% CI of risk difference was greater than the noninferiority margin (NIM) of –20% in both the ITT and per-protocol (PP) analysis sets, the supporting noninferiority of pegcetacoplan to eculizumab.

The mean number of packed RBC units transfused (secondary end point) was 0.6 units (SD = 2.03 units) in the pegcetacoplan arm and 5.1 units (SD = 5.6 units) in the eculizumab arm. The difference between treatments was not tested for statistical significance.

Thrombotic Events

Thrombotic events were not assessed in the efficacy analysis.

Symptoms of PNH

Change from baseline at week 16 in FACIT-Fatigue score was a key secondary end point but was not tested for inferiority or superiority because of prior failure in the testing hierarchy. The LS mean change from baseline at week 16 in the FACIT-Fatigue score in the ITT set (censored for transfusion) was 9.22 points (SE = 1.61 points) in the pegcetacoplan arm and –2.65 points (SE = 2.82 points) in the eculizumab arm, with a between-group difference in LS means of 11.87 points (95% CI, 5.49 to 18.25 points).

A responder analysis that assessed the proportion of patients with at least a 3-point increase in the FACIT-Fatigue score from baseline at week 16 (censored for transfusion) was conducted, and the proportion was 73.2% in the pegcetacoplan arm and 0% in the eculizumab arm. The differences between treatment arms were not tested for statistical significance.

Health-Related Quality of Life

Change from baseline at week 16 in Linear Analogue Scale Assessment (LASA) and European Organisation for Research and Treatment of (EORTC QLQ-C30) scores were secondary end points. The LS mean between-group difference in change from baseline at week 16 in LASA score (censored for transfusion) was 59.1 points (95% CI, 16.9 to 101.3 points). The LS mean between-group differences in LS mean change from baseline at week 16 in EORTC QLQ-C30 global health status, fatigue, pain, and dyspnea scores (censored for transfusion) were, respectively, 18.62 points (95% CI, 0.12 to 37.13 points) points, –20.74 points (95% CI, –35.29 to –6.19 points), –2.76 points (95% CI, –20.36 to 14.85 points), and –14.57 points (95% CI, –29.90 to 0.76 points). The differences between treatment arms for all health-related quality of life (HRQoL) outcomes were not adjusted for multiplicity.

Breakthrough Hemolysis

Breakthrough hemolysis was not assessed in the efficacy analysis.

Complications of PNH Other Than Thrombotic Events

Complications of PNH were not assessed in the efficacy analysis.

Hemolytic Parameters

Change from baseline at week 16 in LDH and ARC were key secondary end points and were tested for noninferiority, according to the hierarchal testing procedure.

The mean LDH level at baseline was 257.5 U/L (SD = 97.6 U/L) in the pegcetacoplan arm and 308.6 U/L (SD = 284.8 U/L) in the eculizumab arm. The LS mean change from baseline at week 16 in LDH level (censored for transfusion) was –14.8 U/L (SE = 42.7 U/L) in the pegcetacoplan arm and –10.1 U/L (SE = 71.0 U/L) in the eculizumab arm, with a between-group difference in LS means of –4.6 U/L (95% CI, –181.3 to 172.0 U/L). Noninferiority was not met because the upper bound of the 95% CI of the between-group difference was not less than the NIM of 20 U/L in both the ITT and PP sets. Results of a supportive analysis based on data uncensored for transfusion were consistent with the primary analysis.

The mean ARC at baseline was 217.5 × 10⁹ cells/L (SD = 75.0 × 10⁹ cells/L) in the pegcetacoplan arm and 216.2 × 10⁹ cells/L (SD = 69.1 × 10⁹ cells/L) in the eculizumab arm. The LS mean change from baseline in ARC at week 16 in the ITT set (censored for transfusion) was –135.8 × 10⁹ cells/L (SE = 6.5 × 10⁹ cells/L)in the pegcetacoplan arm and 27.9 × 10⁹ cells/L (SE = 11.9 × 10⁹ cells/L) in the eculizumab arm, with a between-group adjusted mean difference of –163.6 × 10⁹ cells/L (95% CI, –189.9 to –137.3 × 10⁹ cells/L). Noninferiority was met because the upper bound of the 95% CI of the adjusted mean difference was less than the prespecified NIM of 10 × 10⁹ cells/L in the ITT set, and results were consistent in the PP set. Results of a supportive analysis based on data uncensored for transfusion were also consistent with the primary analysis.

LDH normalization in the absence of transfusion (secondary end point) was achieved in 70.7% of patients in the pegcetacoplan arm and 15.4% of patients in the eculizumab arm, with an adjusted risk difference of 48.8% (95% CI, 32.3% to 65.3%). LDH normalization (uncensored for transfusion) was achieved in 73.2% of patients in the pegcetacoplan arm and 59.0% of patients in the eculizumab arm, with a risk difference of 12.3% (95% CI, 7.0% to 31.5%). The difference between treatment arms was not tested for statistical significance.

Reticulocyte normalization in the absence of transfusion (secondary end point) was achieved in 78.0% of patients in the pegcetacoplan arm and 2.6% of patients in the eculizumab arm, with a risk difference of 66.4% (95% CI, 53.1% to 79.7%). Reticulocyte normalization (uncensored for transfusion) was 80.5% in the pegcetacoplan arm and 17.9% in the eculizumab arm, with a risk difference of 54.8% (95% CI, 38.8% to 70.7%). The difference between treatment arms was not tested for statistical significance.

Health Care Resource Utilization

Health care resource utilization was not assessed in the study.

Harms Results

In the run-in period, treatment-emergent adverse events (TEAEs) were reported in 69 patients (86.3%), but none led to death or discontinuation of the study treatment or the study. A serious TEAE was reported in 1 patient who developed sepsis, which resolved during the run-in period despite continued treatment with pegcetacoplan and eculizumab.

The key harms results from the randomized controlled period of the PEGASUS trial are summarized in Table 2.

TEAEs were reported in 87.8% of patients in the pegcetacoplan arm and 87.2% of patients in the eculizumab arm. The most common TEAEs related to pegcetacoplan (in at least 10% of patients) were diarrhea, injection-site erythema, injection site reaction, and abdominal pain. There was a similar incidence of serious TEAEs in both arms (pegcetacoplan: 17.1%; eculizumab 15.4%). Withdrawal from study treatment due to TEAEs occurred in 3 (7.3%) patients in the pegcetacoplan arm, all due to breakthrough hemolysis. No patients in the eculizumab withdrew from the study treatment due to a TEAE. No deaths were reported in either arm.

The pegcetacoplan arm had a notably higher incidence of injection site–related TEAEs (36.6%) than the eculizumab arm (2.6%). Breakthrough hemolysis was reported less frequently in the pegcetacoplan arm (9.8%) than in the eculizumab arm (23.1%). In the pegcetacoplan arm, there was no report of thrombosis or antipegcetacoplan peptide antibody response, and 1 patient-reported serious treatment-emergent bacterial infection but was unrelated to encapsulated organism. There were no reports of pulmonary hypertension or chronic kidney disease.

Critical Appraisal

Appropriate methods of randomization were used. Although imbalances in some baseline characteristics between treatment groups were noted, none was expected to cause confounding. The open-label design could introduce reporting bias for subjective efficacy end points (i.e., FACIT-Fatigue, LASA, EORTC QLQ-C30) in favour of pegcetacoplan. The high number of major protocol deviations related to study assessment or schedule noncompliance could compromise the completeness and reliability of study data, introducing uncertainties to the results, although the direction and extent of bias are unclear. The statistical analyses were generally well designed, with adequate sample size and appropriate multiplicity adjustments for all key secondary outcomes. Other secondary outcomes were either not tested for statistical significance or not adjusted for multiplicity. No justification was provided for the chosen NIMs, although the NIMs were considered reasonable by the clinical experts. Supportive PP analyses were conducted for end points tested for noninferiority, and results were consistent with the primary ITT analysis. There was a high amount of missing data due to censoring for transfusion. Nonetheless, with respect to the primary end point (change in Hb), results from the sensitivity analyses and supportive analysis using different imputation methods and censoring rules were consistent with the primary analysis, increasing certainty of the findings. It is unclear if Hb improvement is a predictor of long-term clinical outcomes, given that long-term studies are scarce for this rare disease. The reliability, validity, and responsiveness of the FACIT-Fatigue, LASA, and EORTC QLQ-C30 scales have not been previously characterized in patients with PNH, which limits conclusions that can be made on these outcomes.

There was no major concern about the generalizability of the study population, given that the inclusion and exclusion criteria and patient baseline characteristics were consistent with clinical practice. Patients with intolerance to eculizumab were not included; however, this represents a very small population of patients in clinical practice, per clinical expert input. Eculizumab was considered a representative comparator, and the distribution of eculizumab dosing aligns with clinical practice. The follow-up duration was adequate for assessing the efficacy outcomes included in the study, but inadequate for other clinically important outcomes, such as breakthrough hemolysis, survival, thrombosis, and other complications of PNH. The clinical relevance of the FACIT-Fatigue, EORTC QLQ-C30, and LASA instruments is uncertain because they are not used in clinical practice, although they did capture some common symptoms of PNH (e.g., fatigue, dyspnea, pain) reported by patients.

Indirect Comparisons

Description of Studies

The sponsor submitted an anchored matching-adjusted indirect comparison (MAIC) to evaluate the relative efficacy of pegcetacoplan, compared to ravulizumab, in adult patients with PNH previously treated with eculizumab.⁷ The MAIC did not report a systematic literature review to identify relevant studies for inclusion. Two studies were included in the analysis: patient-level data from the PEGASUS study, which compared pegcetacoplan with eculizumab; and aggregate patient data from the ALXN1210-PNH-302 study (referred to as the ALXN study in this report),⁸ which compared ravulizumab with eculizumab. Outcomes analyzed were transfusion avoidance, number of packed RBCs transfused, Hb level stabilization, change from baseline in LDH level, LDH level normalization, fatigue and fatigue symptoms, global health status, and physical functioning. A propensity score model using logistic regression was used to account for between-study differences in patient baseline characteristics. Effect modifiers were matched in the weighting process separate for clinical and hematological outcomes and fatigue and QoL outcomes. Compared with patients who received ravulizumab, a greater proportion of patients who received pegcetacoplan had a history of transfusions in the year before the study (72.2% versus 13.4%), and mean Hb was lower for patients who received pegcetacoplan (8.7 g/dL versus 11.1 g/dL). There was no adjustment for transfusion history or mean Hb in the analysis.

Efficacy Results

After matching and anchoring on eculizumab, treatment with pegcetacoplan compared with ravulizumab was associated with more transfusion avoidance (adjusted difference = 71.4%; 95% CI, 53.5% to 89.3%), more Hb level stabilization (adjusted difference = 75.5%; 95% CI, 56.4% to 94.6%), more LDH level normalization in the absence of transfusions (adjusted difference = 64.0%; 95% CI, 41.8% to 86.1%), and fewer mean units of packed RBCs transfused (adjusted difference = –5.7 units; 95% CI, –7.2 to –4.2 units). In addition, treatment with pegcetacoplan, compared with ravulizumab, was associated with improvements in adjusted difference in mean change from baseline in fatigue (8.2 points; 95% CI, 3.8 to 12.6 points), global health status (9.6 points; 95% CI, 0.1 to 19.0 points), physical functioning (11.5 points; 95% CI, 3.6 to 19.5 points), and fatigue symptoms (–13.3 points; 95% CI, –23.7 to –3.0 points). There was no difference in the mean change from baseline in LDH levels (adjusted mean difference = 0.3 U/L; 95% CI, –154.5 to 155.1 U/L).

Critical Appraisal

The anchored MAIC has several limitations, including the inability to adjust for 2 clinically important effect modifiers (Hb level and history of transfusions) — which differed substantially between the 2 studies at baseline, the heterogeneity between studies regarding duration of follow-up (i.e.,16 weeks for PEGASUS versus 26 weeks for ALXN), the treatment administration schedule, and the dosing regimen. These limitations may introduce unmeasurable confounding in the relative treatment effect estimates, although the direction and extent of bias are unclear. Overall, there is uncertainty in the relative treatment effect estimates favouring pegcetacoplan over ravulizumab.

Other Relevant Evidence

Description of Study

Safety and efficacy results from the 32-week, single-arm, extension period (after the randomized controlled period) for the PEGASUS trial (n = 77), during which all patients received pegcetacoplan, were also submitted by the sponsor and are presented in this report.

Efficacy Results

The results were reported as summary statistics and indicated that efficacy — assessed with Hb level, transfusion avoidance, ARC, LDH level, FACIT-Fatigue Scale score, LASA scores, EORTC QLQ-C30 scores, as well as the number of packed RBC units transfused — was generally maintained in the pegcetacoplan to pegcetacoplan group for another 32 weeks after the randomized controlled period. In the eculizumab to pegcetacoplan group, improvement was consistently observed across all outcomes after initiation of pegcetacoplan, and the patients in this group achieved benefits from pegcetacoplan similar to those seen in the pegcetacoplan to pegcetacoplan group.

Harms Results

The TEAE profile of pegcetacoplan was generally consistent with the randomized controlled period. Hemolysis was reported in 15 (19.5%) patients and led to treatment discontinuation in 2 patients. Thrombosis was reported in 2 (2.6%) patients, but neither was deemed by the sponsor to be related to pegcetacoplan. There were no reports of serious bacterial infection or renal failure. The incidence of pulmonary hypertension was not reported.

Critical Appraisal

The noncomparative design of the extension period precludes the drawing of conclusions about the comparative efficacy of pegcetacoplan and eculizumab beyond 16 weeks. It is difficult to ascertain if the observed effects can be attributed to pegcetacoplan alone because of the lack of control for confounding in a nonrandomized study. No formal statistical testing was conducted, and results were presented using descriptive statistics. The open-label design can influence the reporting of subjective outcomes (FACIT-Fatigue, LASA, EORTC QLQ-C30, harms), introducing uncertainties to the results. Although the study results seem to suggest that the efficacy and safety of pegcetacoplan can be maintained long-term, outcomes such as survival, thrombosis, and other complications of PNH require a much longer duration of follow-up to provide certainty in the results.

Conclusions

In the PEGASUS trial, pegcetacoplan demonstrated a clinically meaningful improvement in Hb level compared with eculizumab in a 16-week randomized controlled period in a study population that was representative of patients with PNH who had clinically significant anemia despite an adequate trial of eculizumab and who had signs of EVH. The evidence strongly suggested that Hb improvement translated into an improvement in transfusion avoidance with pegcetacoplan than with eculizumab. Results also suggested that pegcetacoplan could reduce fatigue, compared with eculizumab, but the magnitude of benefit and its clinical relevance is uncertain. Analyses of hemolytic markers lent support to the ability of pegcetacoplan to reduce EVH and maintain IVH control. The benefits of pegcetacoplan were sustained through week 48 in the extension period, but the single-arm design precludes conclusions about the comparative efficacy of pegcetacoplan and eculizumab beyond week 16. The sponsor-submitted MAIC assessing the comparative efficacy of pegcetacoplan and ravulizumab showed that transfusion avoidance, number of packed RBCs transfused, Hb level stabilization, LDH level normalization, fatigue and fatigue symptoms, global health status, and physical functioning all favoured pegcetacoplan; however, the findings should be interpreted with caution, given the lack of matching of some effect modifiers and the heterogeneity in study designs and populations. The safety profile of pegcetacoplan was generally similar to that of eculizumab, but with a higher incidence of nonserious injection site–related reactions and diarrhea. A longer duration of follow-up is required to provide certainty about the incidence of breakthrough hemolysis, thrombosis, and survival with pegcetacoplan treatment.

Introduction

Disease Background

PNH is an extremely rare chronic disease characterized by IVH and heterogenous signs and symptoms that include hemoglobinuria, anemia, abdominal pain, fatigue, dyspnea, dysphagia, and erectile dysfunction.¹ Complications of PNH include thrombosis, chronic kidney disease, and pulmonary hypertension.² In Canada, the median age of disease onset has been estimated at 43 years.¹ Although the incidence of PNH has not been extensively characterized, 1 study in the UK estimated an annual incidence of clinical PNH of approximately 0.13 per 100,000 persons.³ PNH is a consequence of an acquired genetic mutation, leading to clonal expansion of hematopoietic stem cells that produce abnormal RBCs, leukocytes, and platelets deficient in glycophosphatidylinositol anchor proteins.² These abnormal RBCs are susceptible to complement-mediated IVH. PNH may develop as subclinical PNH, with no substantial clinical findings and no bone marrow abnormalities;⁹ as hemolytic PNH, typically with a white blood cell clone size of greater than 10%; or in association with a bone marrow disorder, such as aplastic anemia or myelodysplastic syndrome, which is often accompanied by smaller clone sizes (i.e., the proportion of blood cells deficient in glycophosphatidylinositol anchor protein).¹ Studies examining the survival of patients with PNH after diagnosis show a range of median survival, from 14.6 years to 32 years,^10,11 whereas results from a study of patients with PNH treated with eculizumab suggested that their survival was similar to that of age-matched controls.¹²

It is estimated that 20% to 30% of patients have ongoing and clinically significant anemia, despite standard-of-care treatment with C5 inhibitors, per input from clinical experts consulted by CADTH. According to the Canadian PNH Network, there is no consensus on the method to assess response to anticomplement treatment, and the group suggested that response evaluation be based on symptoms, transfusion requirements, LDH level, and complete blood count parameters.¹ Response categories were proposed by DeZern et al. (2013) as follows¹³:

• complete response, defined as transfusion independence, normal Hb for age and sex, absence of symptoms, LDH less than 1.5 times the ULN

• good partial response, defined as decreased transfusions from pretreatment status, LDH less than 1.5 times the ULN, no thromboembolism after the start of therapy, and Hb remaining low for age and sex

• suboptimal response, defined as unchanged transfusion needs and persistent or new symptoms after the start of therapy.

An international working group proposed a response classification system based on similar parameters (Table 42 in Appendix 4).¹⁴

The Canadian PNH Network noted the following causes of eculizumab failure¹:

• breakthrough (intravascular) hemolysis, the most common cause of treatment failure; it can be due to situational events that amplify complement activity (e.g., surgery, infection) or insufficient dosing of eculizumab, which usually occurs near the end of each dosing cycle

• C3-mediated extravascular hemolysis, an iatrogenic effect of C5 inhibitor treatment caused by increased C3 disposition on erythrocytes, resulting in erythrocytes being opsonized with C3 fragments and destroyed via extravascular destruction

• the development of human-antihuman or eculizumab-neutralizing antibodies (low incidence)

• C5 genetic polymorphism, which prevents eculizumab from binding to its target molecule and is mostly found in patients of Japanese descent (low incidence).

The clinical experts noted that ongoing anemia could also be caused by issues such as insufficient bone marrow function, renal insufficiency, and deficiency in iron, folate, and vitamin B₁₂, and by gastrointestinal bleed, which should be thoroughly assessed before the underlying cause(s) of C5 inhibitor treatment failure and appropriate management strategies can be determined.

Standards of Therapy

For patients with subclinical PNH (i.e., asymptomatic and no bone marrow failure), no treatment intervention is usually required and they are managed with watchful waiting.¹⁵ For patients with hemolytic PNH and associated bone marrow disorders, the only curative therapy is allogeneic stem cell transplant; however, due to significant morbidities and mortality, hematopoietic cell transplant is generally reserved for patients with severe bone marrow failure due to bone marrow disorders or patients with PNH complications who are unresponsive to C5 inhibitors.^15,16

According to the clinical experts consulted by CADTH, in patients diagnosed with hemolytic PNH who have high disease activity (i.e., symptomatic and LDH above 1.5 times the ULN [indicative of clinically significant IVH]), the current standard of care in the first-line setting are terminal C5 inhibitors (i.e., eculizumab, ravulizumab), which have been shown to effectively reduce uncontrolled complement activation and its complications. In patients who have an inadequate response to C5 inhibitors, clinical management can vary, depending on the underlying cause of treatment failure. According to the Canadian PNH Network¹ and input from the clinical experts, current treatment approaches in Canada for these patients are as follows:

• Breakthrough (intravascular) hemolysis: If due to situational events that amplify complement activity, address the underlying cause of the breakthrough event. If due to insufficient dosing of eculizumab, increase the dose of eculizumab (e.g., 1,200 mg every 14 days) or shorten infusion intervals (e.g., every 12 days). This should lead to appropriate complement inhibition in 98% of patients.¹⁷

• C3-mediated EVH: According to the clinical experts, before the approval of pegcetacoplan, there was no approved subsequent therapy for patients with ongoing anemia due to EVH in Canada. The treatment approach is to provide best supportive care (e.g., RBC transfusion, corticosteroids, splenectomy, danazol, epoetin alfa) while continuing C5 inhibitor treatment (to prevent life-threatening IVH), although many best supportive care therapies are associated with toxicities. Alternatively, patients could be referred to clinical trials of proximal complement inhibitors (e.g., C3 or factor D inhibitor). In patients with concurrent bone marrow insufficiency, immunosuppressive therapy should be considered as an add-on therapy.

• C5 genetic polymorphism: Referral to clinical trials of proximal complement inhibitors should be considered because patients with this genetic trait are not expected to respond to C5 inhibitor treatments.

Vaccination, with or without prophylactic antibiotics, for meningococcal infections is recommended for all patients receiving complement inhibitors.¹

The clinical experts noted that the goals of treatment of PNH include increasing Hb level, avoiding transfusion, preventing hemolysis and chronic complications of PNH, and improving QoL and life expectancy.

Drug

Pegcetacoplan is a proximal complement inhibitor that binds to C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation and inhibiting complement-mediated extravascular and IVH.

This is the first review for pegcetacoplan by CADTH. Pegcetacoplan was granted a Health Canada Notice of Compliance for the indication of treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor. The sponsor is seeking reimbursement of pegcetacoplan for that indication.

Per the product monograph, the recommended dosage of pegcetacoplan is 1,080 mg twice weekly by subcutaneous infusion with a syringe system infusion pump administered by a health care professional, the patient, or a caregiver.⁴ It is recommended that pegcetacoplan be administered in addition to the patient’s current dose of C5 inhibitor treatment for the first 4 weeks to minimize the risk of hemolysis due to abrupt treatment discontinuation.⁴ A dosage increase to 1,080 mg every third day may be considered if the LDH level is greater than 2 times the ULN with twice-weekly dosing.⁴ It is recommended that treatment with pegcetacoplan continue for the patient’s lifetime, unless discontinuation is clinically indicated.⁴

The key characteristics of treatments for PNH are summarized in Table 3.

Table 3: Key Characteristics of Pegcetacoplan, Eculizumab, and Ravulizumab

C3 = complement component 3; C5 = complement component 5; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; SC = subcutaneous; ULN = upper limit of normal.

^aHealth Canada–approved indication.

^bDose escalation of eculizumab to 1,200 mg every 14 weeks or reduction of dosing interval to 900 mg every 12 days is considered in patients with PNH experiencing breakthrough hemolysis in clinical practice, per the Canadian PNH Network.¹

Sources: Product monographs of pegcetacoplan,⁴ eculizumab,¹⁸ and ravulizumab.¹⁹

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

The Canadian Association of PNH Patients and the Aplastic Anemia & Myelodysplasia Association of Canada submitted a joint input for this review. Information was gathered through 1-on-1 interviews with 6 individuals diagnosed with PNH living in Canada and from the scientific literature. The patient group expressed the following negative impacts of PNH: persistent anemia (manifested as fatigue or extreme fatigue), hemolysis leading to thrombosis, employment absenteeism for patients and caregivers, dependence on frequent blood transfusions, and reduced QoL. According to the input, patients with PNH, particularly those experiencing EVH, need alternative treatment options because of the inability of eculizumab or ravulizumab to thoroughly control IVH and prevent EVH. The patient group also expressed the need for therapies to improve anemia, reduce or eliminate transfusion requirements, and improve fatigue and QoL. Among 3 patients who have used pegcetacoplan, they noted an immediate normalization of hematological parameters, easier administration (self-administered easily through subcutaneous infusion twice weekly at home) than with eculizumab or ravulizumab (visits for IV transfusions), reduced blood transfusions, and improved physical functioning and QoL. Some patients stated the importance of proper injection training.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of PNH.

Unmet Needs

The clinical experts noted that C5 inhibitors are effective in controlling IVH; however, not all patients respond to treatment. While on C5 inhibitor treatment, some patients remain anemic, with chronic hemolysis and/or acute hemolytic crisis, requiring ongoing transfusions despite no evidence of bone marrow failure. The clinical experts also noted that none of the currently approved treatments addresses C3-mediated EVH, and clinical trial enrolment is the only alternative. Although best supportive care measures are available to patients who have an inadequate response to C5 inhibitors, they are not always effective and are associated with significant toxicities, according to the clinical experts. Transfusion, the mainstay supportive measure, is associated with complications such as risk of iron and fluid overload, infection, and poor QoL, and access is limited by blood shortages. Transfusion is only performed when a patient is severely anemic (i.e., Hb less than 7 g/dL to 8 g/dL). Corticosteroids are associated with a lot of side effects (e.g., osteoporosis, corticosteroid dependence, adrenal insufficiency, opportunistic infections, dyspepsia), and epoetin alfa is associated with a theoretical risk of thrombosis. Bone marrow transplant is a curative treatment for patients with PNH; however, the clinical experts noted that few patients are candidates and bone marrow transplant is associated with high morbidity and mortality.

The clinical experts noted there is a need for treatments that are effective in patients who have insufficient control of IVH despite treatment with eculizumab, that address the issue of C3-mediated EVH, and that can be used in patients with intolerance to C5 inhibitors (although rare in clinical practice) or difficult venous access.

Place in Therapy

The clinical experts noted that pegcetacoplan is a proximal C3 inhibitor and has a mechanism of action in addition to existing treatments because C3 is a more upstream effector than C5 in the complement activation pathway. However, the clinical experts anticipated that pegcetacoplan will mainly serve as a second-line treatment in patients who are intolerant to C5 inhibitors or who have an inadequate response to C5 inhibitors. The clinical experts noted that C5 inhibitors will likely remain the preferred treatment for PNH in a first-line setting because clinicians have much more experience with C5 inhibitors than with pegcetacoplan in treatment-naive patients.

The clinical experts did not expect pegcetacoplan to cause a major shift in the current treatment paradigm because it is reserved for second-line and will only be used in select patients who are expected to benefit from treatment, based on clinical judgment by clinicians and individual patient needs. The clinical experts noted the drug would instead allow for a greater proportion of patients with improved treatment outcomes.

Patient Population

The clinical experts noted that appropriate candidates for pegcetacoplan treatment include patients with PNH who have persistent anemia (with or without history of ongoing blood transfusion needs) and evidence of EVH, despite an adequate trial of C5 inhibitor treatment; patients with intolerance to a C5 inhibitor (uncommon in clinical practice); and patients with a rare C5 genetic polymorphism (mainly in patients of Japanese descent). The clinical experts noted that pegcetacoplan could potentially be considered in patients who are geographically isolated or who have poor venous access. Patient with a PNH clone size of less than 10% should not receive pegcetacoplan, according to the clinical experts.

The clinical experts noted the following laboratory tests that help inform eligibility assessment: complete blood count, LDH, Coombs test, and blood tests for end organ damage; complement testing is not readily available at the moment and treatment decisions are not based on it. The clinical experts noted that C3-loading is demonstrated in most patients receiving eculizumab, but only 10% to 20% of patients developed sufficient C3-loading to cause clinically significant anemia. According to the clinical experts, suspicion of C3-mediated EVH would come when there are ongoing low Hb levels, elevated reticulocyte counts and bilirubin levels (indicating presence of hemolysis), but normal or slightly elevated LDH levels (indicating reasonable control of IVH). Additional laboratory tests are required to rule out other causes of ongoing anemia, such as IVH, inadequate bone marrow function, iron or vitamin B₁₂ deficiency, and gastrointestinal bleed. The clinical experts noted that because all patients with PNH are expected to be under the care of a PNH expert, all of the above factors would be taken into consideration when the treating physician selects suitable candidates for pegcetacoplan. The clinical experts considered ongoing anemia with Hb levels of less than 10 g/dL to be indicative of a suboptimal response to a C5 inhibitor, recognizing that there is variability in the cut-offs used by other clinicians.

The clinical experts noted that it is possible that clinicians may fail to identify patients who can benefit from a switch to pegcetacoplan treatment, although the chance is low because all patients are presumably treated by PNH experts.

Assessing Response to Treatment

The clinical experts noted that a clinically meaningful treatment response would include improvement in hemolytic parameters (LDH, bilirubin) and Hb level, reduced transfusion needs, and improved QoL. The clinical experts added that normalization of laboratory parameters may not be a realistic goal in every patient; treatment response is generally determined, per clinical judgment, by the treating physician, based on a global assessment of all patient parameters, chronology of symptoms, and laboratory results.

The clinical experts noted that follow-up assessments are usually conducted every 3 months, although more frequent follow-up visits are warranted for patients who have recently switched to pegcetacoplan for closer monitoring of symptoms and laboratory parameters until patients become stabilized. Patients are also monitored with PNH flow cytometry every 6 months to 12 months for changes in their clone size.

Discontinuing Treatment

The clinical experts noted that once a patient is switched to pegcetacoplan, it is unlikely that pegcetacoplan would be discontinued unless 1 of the following occurs: treatment failure (persistent anemia and ongoing transfusion needs) necessitating a switch to a more effective treatment, intolerance to pegcetacoplan, or resolution of disease after bone marrow transplant.

Prescribing Conditions

The clinical experts noted that the diagnosis, treatment, and monitoring of patients with PNH should be managed by hematologists. Given the rarity of the disease, consultation with hematology specialists who have expertise in the management of PNH is encouraged.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section at the end of this report.

One clinician group, the Canadian PNH Network, submitted input for this review based on contributions from 11 clinicians. The group noted that the current standard of care comprises C5 inhibitors (i.e., eculizumab and ravulizumab), which act via terminal complement blockade. They noted that although C5 inhibitors are not curative treatment, these treatments have been shown to be effective in controlling IVH, leading to significant improvement in fatigue, QoL, transfusion dependence, thrombosis, and overall survival. The only curative treatment for PNH is allogeneic hematopoietic stem cell transplant and is available to patients with predominant or progressive bone marrow failure or to eligible patients with evidence of clonal evolution. However, the group highlighted 3 unmet needs: some patients do not have access to standard care due to highly restrictive reimbursement criteria; eculizumab has a high treatment burden because it requires venous access for administration every 2 weeks and nurse visits; and, despite treatment, approximately one-third of patients remain anemic due to EVH and some are transfusion-dependent. The group explained that drugs that exploit proximal complement blockade, such as C3 inhibitors, address EVH risk, significantly increase Hb, and improve QoL. Regarding its place in therapy, the group stated that pegcetacoplan is the first C3 inhibitor that protects against EVH, and it would fit into the current treatment landscape as an alternative (i.e., switch) option for patients with no or inadequate response or intolerance to eculizumab or ravulizumab. Eligible patients would include those with persistent anemia (Hb less than 10.5 g/dL or perhaps higher, if symptomatic) despite stable doses of eculizumab or ravulizumab who have had other causes of ongoing anemia (e.g., breakthrough hemolysis or bone marrow failure) ruled out. The group indicated that a clinically meaningful response to treatment would be sustained control of LDH level (i.e., below 1.5 times the ULN), an increase in Hb (or possibly Hb stabilization without further need of transfusion), and improvement in anemia-related symptoms. Treatment discontinuation should be considered in patients who have AEs that preclude ongoing therapy (e.g., recurrent breakthrough hemolysis, issues with effective self-administration, intolerable pain from injection). The group indicated that the treatment and monitoring of patients should ideally be done by clinicians who specialize in the area, although patients can self-administer pegcetacoplan at home or anywhere they prefer.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ARC = absolute reticulocyte count; C3 = complement component 3; C5 = complement component 5; CDEC = CADTH Canadian Drug Expert Committee; EVH = extravascular hemolysis; FACIT = Functional Assessment of Chronic Illness Therapy; Hb = hemoglobin; IVH = intravascular hemolysis; LDH = lactate dehydrogenase; pCPA = pan-Canadian Pharmaceutical Alliance; PLA = product listing agreement; PNH = paroxysmal nocturnal hemoglobinuria; PSP = Patient Support Program; TEAE = treatment-emergent adverse event; ULN = upper limit of normal.

Clinical Evidence

The clinical evidence included in the review of pegcetacoplan is presented in 3 sections. The first section, the systematic review, includes the pivotal study provided in the sponsor’s submission to CADTH and Health Canada, as well as studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of pegcetacoplan (54 mg/mL) solution for subcutaneous infusion for the treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor.

Methods

Studies selected for inclusion in the systematic review will include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented below was established before the granting of a Notice of Compliance from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; C5 = complement component 5; HRQoL = health-related quality of life; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁰

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was pegcetacoplan. The clinical trials registries searched were the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on September 26, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on January 25, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²¹ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy. Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

One study (PEGASUS)⁵ was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of the Included Study

AE = adverse event; ARC = absolute reticulocyte count; AV = atrioventricular; C3 = complement component 3; ECG = electrocardiogram; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT = Functional Assessment of Chronic Illness Therapy; Hb = hemoglobin; LASA = Linear Analogue Scale Assessment; LDH = lactate dehydrogenase; NYHA = New York Heart Association; PNH = paroxysmal nocturnal hemoglobinuria; QTcF = QT interval corrected for heart rate using Fridericia’s formula; RBC = red blood cell; SAE = serious adverse event; ULN = upper limit of normal; WDAE = withdrawal due to adverse event.

Note: Three additional reports were included (FDA report,²² Cella et al. (2022),²³ PEGASUS Clinical Study Report [16 weeks]⁶).

^aDiagnosis confirmed with high-sensitivity flow cytometry.

^bIncluding N. meningitidis types A, C, W, Y, and B.

^cIncluding unexplained syncope or syncope from an uncorrected cardiac etiology.

^dIncluding Mobitz type II second-degree AV block, 2:1 AV block, and high-grade AV block.

^ePatients with an implanted pacemaker or implantable cardiac defibrillator with backup pacing capabilities were allowed.

^fOnly secondary end points pertaining to the randomized controlled period were summarized. Additional secondary end points pertaining to the open-label period, which included change from baseline and change from week 17 to week 48 with respect to Hb level, ARC, LDH level, FACIT-Fatigue Scale score, LASA score, EORTC QLQ-C30 score, as well as the number of packed RBC units transfused during open-label pegcetacoplan.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Description of Studies

One study (PEGASUS)⁵ met the inclusion criteria for the CADTH systematic review. The PEAGSUS trial was a phase III, open-label, randomized, active-controlled trial that aimed to compare the efficacy and safety of pegcetacoplan with eculizumab in adults with PNH who continued to have Hb levels of less than 10.5 g/dL despite treatment with eculizumab (N = 80). The study was conducted at 44 sites in 11 countries (including 2 sites in Canada). It was initiated on June 14, 2018, and completed on August 13, 2020. The study consisted of the following 5 periods:

• Screening period (4 weeks) — study eligibility assessment.

• Run-in period (week –4 to day –1) — all patients received pegcetacoplan in addition to eculizumab at the established dose to avoid a period of insufficient complement inhibition.

• Randomized controlled period (week 1 to week 16) — patients were randomized in a 1:1 ratio using interactive response technology to receive either pegcetacoplan or eculizumab monotherapy. Randomization was stratified by the number of packed RBC transfusions in the previous 12 months (less than 4 versus at least 4), and the platelet count at screening (less than 100,000/mm³ versus at least 100,000/mm³).

• Open-label pegcetacoplan period (week 17 to week 48) — All patients received pegcetacoplan monotherapy. For patients who received eculizumab in the randomized controlled period, they first entered a 4-week run-in period during which pegcetacoplan was given in addition to eculizumab to ensure sufficient complement inhibition. They then received pegcetacoplan monotherapy for the remainder of the pegcetacoplan period.

• Follow-up period (week 49 to week 60) — Patients continued to be monitored for an additional 12 weeks in the follow-up period unless they opted to transition to an open-label extension study.

Efficacy and safety were assessed in the 16-week randomized controlled period, and the results are summarized in this section. The primary efficacy end point was change from baseline at week 16 in Hb level, and the key secondary efficacy end points included transfusion avoidance, change from baseline at week 16 in ARC, LDH, and FACIT-Fatigue Scale score. Results of the open-label pegcetacoplan period and follow-up period are presented in the Other Relevant Evidence section of this report.

Figure 2: Study Design Schematic of the PEGASUS Trial

APL-2 = pegcetacoplan; ecu = eculizumab; Excl = exclusion; Incl = inclusion; Maint. = maintenance; W = week.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria in the PEGASUS trial are summarized in Table 6. The study enrolled adults with PNH who were on a stable dose of eculizumab for at least 3 months with an Hb level of less than 10.5 g/dL, an ARC level above the ULN, a platelet count above 50,000/mm³, and an absolute neutrophil count above 500/mm³. Patients who had a history of bone marrow transplant, hereditary complement deficiency, or were treated with iron, folic acid, and vitamin B₁₂ at a stable dose for less than 4 weeks were excluded. Patients with certain cardiovascular diseases or who were receiving QT-prolonging medications that, in the sponsor’s opinion, could potentially confound the study’s cardiac safety outcomes were also excluded from the study.

Baseline Characteristics

A summary of baseline patient demographics and disease characteristics is shown in Table 7. The study population had a mean age of 48.8 years (SD = 16.0 years). The majority of patients were female and white (both 61.3%). Patients had a mean time since diagnosis of 10.1 years (SD = 8.6 years) and had received eculizumab for a mean duration of 1,808.7 days (SD = 1,447.6 days). Most patients (70.0%) received eculizumab 900 mg every 2 weeks (i.e., Health Canada–approved maintenance dose), although higher doses (1,200 mg or 1,500 mg every 2 weeks) or more frequent dosing of eculizumab (900 mg every 11 days) were also used. Fifty-five percent of patients had received at least 4 transfusions in the previous 12 months. Patients had a mean Hb level of 8.7 g/dL (SD = 1.0 g/dL), mean LDH level of 282.42 U/L (SD = 211.0 U/L), mean ARC of 216.9 × 10⁹ cells/mL (SD = 71.7 × 10⁹ cells/mL), mean indirect bilirubin level of 33.8 µmol/L (SD = 25.8 µmol/L), and mean haptoglobin level of 0.135 g/L (SD = 0.1206 g/L).

Overall, the baseline demographics and disease characteristics were balanced between treatment arms, except the mean time since diagnosis was shorter in the pegcetacoplan arm (mean = 8.74 years; SD = 7.36 years) than the eculizumab arm (mean = 11.7 years; SD = 9.58 years). The proportion of patients on eculizumab at 900 mg every 2 weeks before the study (63.4%) and the mean LDH levels (257.5 U/L; SD = 97.6 U/L) were lower in the pegcetacoplan arm compared eculizumab arm (76.9% on eculizumab 900 mg every 2 weeks; mean LDH level = 308.6 U/L; SD = 284.8 U/L). A higher proportion of patients had a history of thrombosis in the pegcetacoplan arm (36.6%) than the eculizumab arm (25.6%).

Table 7: Summary of Baseline Characteristics in the PEGASUS Trial — Randomized Controlled Period (ITT)

ARC = absolute reticulocyte count; ITT = intention to treat; LDH = lactate dehydrogenase; SD = standard deviation.

^aAll baseline disease characteristics were recorded at day –28 (first dose of pegcetacoplan in the run-in period). The mean value for Hb included local and central laboratory values; all other laboratory parameters were based on central laboratory values.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Interventions

Pegcetacoplan was dosed at 1,080 mg twice weekly via subcutaneous infusion. A dose increase of pegcetacoplan to 1,080 mg every third day was allowed in patients on pegcetacoplan monotherapy if the LDH level was at least 2 times above the ULN. Eculizumab was administered based on the patient’s dose established before study entry (900 mg, 1,200 mg, or 1,500 mg every 2 weeks, or 900 mg every 11 days) via IV infusion; no dose change of eculizumab was allowed during the study.

No blinding of interventions occurred in the study. Pegcetacoplan was self-administered by patients using a syringe system infusion pump, and infusion training was provided in the run-in period. Eculizumab infusion could be performed at home, at a local infusion centre, or by a local hematologist.

Concomitant medications allowed in the study included antibiotics (prophylaxis and treatment), iron supplements (if initiated before study enrolment and dosage remained stable), iron chelation (if tolerance was previously established), and QT-prolongation drugs (if dosage was stable for at least 3 weeks before enrolment). Phlebotomy or venesection were allowed if Hb was within the normal range. These medications and procedures were prohibited if the predefined criteria were not met. Transfusions were to be given if Hb level was less than 7 g/dL without symptoms or less than 9 g/dL with symptoms. In the event that patients did not meet the criteria but a transfusion was deemed necessary by the investigators, a transfusion could be given but was considered a protocol deviation.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8 and summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

ARC = absolute reticulocyte count; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT = Functional Assessment of Chronic Illness Therapy; Hb = hemoglobin; HRQoL = health-related quality of life; LASA = Linear Analogue Scale Assessment; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; RBC = red blood cell.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Efficacy Outcomes

Unless otherwise specified, baseline was defined as the average of measurements recorded before the first dose of the investigational product (i.e., before the start of the run-in period [week –4]) and assessments were conducted at all study visits during the run-in period (i.e., weeks –4, –3, and –2), and the randomized controlled period (i.e., weeks 1, 2, 4, 6, 8, 12, and 16).

Hb Level

Hb level was assessed at each study visit based on samples collected before study drug administration and analyzed in a central laboratory. The change from baseline at week 16 in Hb level was the primary efficacy end point. Secondary end points related to Hb level included Hb response in the absence of transfusions at week 16 (with response defined as an increase of at least 1 g/dL in Hb from baseline) and Hb normalization in the absence of transfusions at week 16 (with normalization defined as the Hb level being above the lower limit of the normal range [i.e., 12 g/dL in females and 13.6 g/dL in males]).

Hb level is used in the diagnosis and monitoring of disease activity of PNH,¹⁶ and low levels of Hb indicate anemia. The validity, reliability, responsiveness, or MID estimates of these parameters have not been studied in patients with PNH. It has been proposed that Hb level is a strong surrogate biomarker for clinical benefits in patients with sickle cell disease receiving stem cell or gene therapy.^24,25 It has also been proposed that an increase in Hb of 1 g/dL from baseline indicates disease improvement in patients with sickle cell disease.^24,25

Transfusions

Transfusion avoidance, a key secondary efficacy end point, was defined as the proportion of patients who did not require a transfusion during the randomized controlled period. Patients were to receive a transfusion if Hb level was less than 7 g/dL without symptoms or less than 9 g/dL with symptoms, if deemed necessary by the investigators. The number of packed RBC units transfused was assessed as a secondary efficacy end point.

Symptoms of PNH

The change from baseline at week 16 in FACIT-Fatigue Scale score was a key secondary efficacy end point. The instrument was administered at each study visit, except at week –3.

The FACIT-Fatigue Scale is a 13-item, patient-reported, fatigue-specific, QoL questionnaire that uses a 5-point Likert scale. It assesses tiredness, weakness, and difficulty conducting usual activities as a result of fatigue over the previous week. The total score ranges from 0 (extreme fatigue) to 52 (no fatigue). A study demonstrated content validity of this instrument in 29 treatment-naive patients with PNH receiving a C5 inhibitor in the UK, US, France, and Spain.²⁶ However, evidence for other types of validity, reliability, and responsiveness have not been previously assessed in this patient population. A study established a clinically important difference of 5 points in treatment-naive patients with PNH receiving eculizumab.²⁷

HRQoL or QoL

The change from baseline at week 16 in LASA score and EORTC QLQ C-30 were secondary efficacy end points. The instruments were administered at each visit, except at week –3.

The LASA used in the trial was a 3-item, self-administered questionnaire that assessed QoL; it appeared to be an adaptation of the LASA reported by Locke et al. (2007).²⁸ More details on the original version of the LASA and its properties can be found in Table 41 in Appendix 4. The version used in this study included 3 visual analogue scales that assess energy level, activities of daily living, and overall QoL over the previous week. Each scale employed a 0 to 100 scale, and a combined score (range, 0 to 300) was computed. A higher score indicates higher functioning. The validity, reliability, responsiveness, and MID estimates of this instrument have not been previously studied in patients with PNH.

The EORTC QLQ-C30, a 30-item, patient-reported, cancer-specific questionnaire that evaluates HRQoL in patients by assessing 3 domains: function, symptom, and global health status/QoL. There are subscales in the function domain (physical, role, emotional, cognitive, and social functioning) and the symptom domain (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and outcome score for each scale is computed using a linear transformation of the raw score, such that scores range from 0 to 100. A higher score for the function and symptom scales represents a higher (better) level of functioning and a higher (worse) level of symptoms, respectively. A higher score for global health status/QoL represents a better level of global health status. A study demonstrated content validity of this instrument in 29 treatment-naive-patients with PNH who received a C5 inhibitor in the UK, US, France, and Spain;²⁶ however, evidence for other validity measures, reliability, responsiveness, and MID estimates have not been established in this patient population.

Intravascular Hemolysis

Serum LDH was assessed at each study visit based on samples collected before study drug administration and analyzed in a central laboratory. The change from baseline at week 16 in LDH level was a key secondary efficacy end point.

LDH is a marker of IVH²⁹ and is used in the diagnosis and monitoring of disease activity of PNH.¹⁶ It has been reported that an LDH level of at least 1.5 times above the ULN is associated with 4.8-fold increase in risk of mortality³⁰ and an increased risk of thromboembolism (odds ratio = 7.0; P = 0.013)³¹ based on data from a national South Korean PNH registry that includes patients who are eculizumab-naive (N = 301).

Extravascular Hemolysis

The change from baseline at week 16 in ARC was a key secondary efficacy end point. Reticulocyte normalization in the absence of transfusions at week 16 was a secondary efficacy end point, with normalization defined as a reticulocyte count being below the ULN (i.e., 120 × 10⁹ cells/L). The change from baseline at week 16 in indirect bilirubin and haptoglobin levels were secondary end points. Reticulocyte count and indirect bilirubin level were assessed at each study visit, whereas haptoglobin was assessed at weeks –4, 1, 4, 8, 12, and 16. The samples were collected before study drug administration and were analyzed in a central laboratory.

Reticulocyte, indirect bilirubin, and haptoglobin are hemolytic markers used in the diagnosis and monitoring PNH disease activity.¹⁶ Elevated reticulocyte count is an indicator of marrow compensatory response that produces RBCs in the presence of hemolysis.²⁹ Bilirubin is produced from the breakdown of Hb and is usually elevated in hemolysis.²⁹ Haptoglobin functions as a scavenger that binds free Hb from lysed RBCs, and reduction in haptoglobin level is a marker of hemolysis.³² The validity, reliability, responsiveness, and MID estimates of these measures have not been studied in patients with PNH.

Harms Outcomes

Safety assessments were conducted at each study visit to assess TEAEs, serious TEAEs, withdrawal due to AEs, laboratory parameters, and electrocardiogram. Survival (death events), thrombotic events, hemolysis, and renal failure are reported in the Harms section.

Breakthrough hemolysis was defined as at least 1 of the following in the presence of LDH elevation to at least 2 times the ULN after prior LDH reduction to below 1.5 times the ULN on therapy: a new or worsening symptom or sign of IVH (fatigue, hemoglobinuria, abdominal pain, dyspnea); anemia (Hb less than 10 g/dL); or major adverse vascular events, including thrombosis, dysphagia, or erectile dysfunction).

Statistical Analysis

A summary of the statistical analysis of efficacy outcomes in the PEGASUS trial is shown in Table 9.

Sample Size and Power Calculations

A sample size calculation determined that 64 patients (32 per treatment arm) was required to demonstrate a statistically significant difference between pegcetacoplan and eculizumab with respect to the change from baseline in Hb level at week 16 (primary end point) at a 2-sided significance level of 0.05 with a power of 90%, assuming a treatment difference between pegcetacoplan and eculizumab of 1 g/dL and a SD for the change from baseline of 1.2 g/dL. The study aimed to enrol at least 70 patients to account for loss of power due to discontinuations.

Table 9: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; ARC = absolute reticulocyte count; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT = Functional Assessment of Chronic Illness Therapy; Hb = hemoglobin; ITT = intention to treat; LASA = Linear Analogue Scale Assessment; LDH = lactate dehydrogenase; mITT = modified intention to treat; MMRM = mixed model for repeated measures; PP = per protocol; RBC = red blood cell.

^aStratification factors: number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), and platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³).

Source: PEGASUS Statistical Analysis Plan (16 weeks).³³

Statistical Analysis for Primary Efficacy End Point

Statistical Model

In the primary analysis, the difference in the mean change from baseline in Hb level at week 16 between treatment arms in the ITT set was tested at a 2-sided significance level of 0.05 using a mixed model for repeated measures (MMRM). The model was stratified by fixed categorical effects, including treatment group, study visit, stratification factors (number of packed RBC transfusions in the previous 12 months [less than 4 versus at least 4], platelet count at screening [less than 100,000/mm³ versus at least 100,000/mm³]), study visit by treatment group interaction, and continuous fixed covariate of Hb level, assuming an unstructured covariance matrix.

Handling of Intercurrent Events and Missing Data

Transfusions, discontinuation of study treatment, and withdrawal from the study during the randomized controlled period were considered intercurrent events in the study. Transfusions or withdrawals from the study were handled using a while-on-treatment strategy in which all measurements after the intercurrent events were censored. Discontinuations of study treatment were handled using a treatment-policy strategy in which all observed values were used regardless of the occurrence of intercurrent events. Missing data were implicitly imputed by the MMRM based on the assumption that data were missing at random.

Subgroup, Sensitivity, and Supportive Analyses

The following prespecified subgroup analyses were conducted for the primary end point: the number of packed RBC transfusions received in the previous 12 months, platelet count at screening, sex, and race; however, none of these analyses was of interest to this review, according to the systematic review protocol.

Two prespecified sensitivity analyses were conducted to examine departures from assumptions regarding missing data, including the control-based pattern imputation method and a tipping point analysis, both of which assume missingness not at random.

Five prespecified supportive analyses were conducted: PP set; modified ITT (mITT) set; completer set; ITT set using all available data (regardless of whether the Hb level was measured after a transfusion); and nonparametric randomization-based analysis of covariance in the ITT set. Refer to the Analysis Populations section for population definitions.

Statistical Analysis for Secondary Efficacy End Points

Multiplicity Adjustment

If the primary end point was met, the key secondary end points were tested for noninferiority using a closed testing procedure in the following hierarchical order: transfusion avoidance, change from baseline at week 16 in ARC, change from baseline at week 16 in LDH level, and change from baseline at week 16 in FACIT-Fatigue score. It was preplanned that if all key secondary end points demonstrated noninferiority, superiority was then assessed for all key secondary end points, in the same hierarchical order, using a closed testing procedure at a 2-sided significance level of 0.05. No multiplicity adjustment was performed for any other secondary end points.

Noninferiority Margin

Pegcetacoplan was considered noninferior to eculizumab in a key secondary end point when the following criteria were met:

• Transfusion avoidance — the lower bound of the 95% CI was greater than the NIM of −0.2 (i.e., –20%)

• ARC — the upper bound of the 95% CI for the treatment difference was less than the NIM of 10 × 10⁹ cells

• LDH — the upper bound of the 95% CI for the treatment difference was less than the NIM of 20 U/L

• FACIT-Fatigue score — the lower bound of the 95% CI for the treatment difference was greater than the NIM of –3 points.

Statistical Model and Test

Continuous secondary end points (i.e., ARC, LDH, FACIT-Fatigue score, EORTC QLQ-C30 score, LASA score, indirect bilirubin, and haptoglobin) were analyzed in the ITT set using the same statistical approach as in the primary analysis of the primary end point, except using their own baseline value as a covariate. For categorical secondary end points (i.e., transfusion avoidance, Hb response, Hb normalization, and reticulocyte normalization), the primary analysis was performed in the ITT population. The risk difference between treatments and the respective 95% CI were constructed using the stratified Miettinen-Nurminen method.

The methods of handling intercurrent events and missing data were the same as in the primary analysis of the primary end point. Of note, in the transfusion avoidance analysis, patients who did not have a transfusion but withdrew from the study were considered to have had a transfusion.

For all key secondary end points, supportive analyses (PP, mITT sets) and an additional analysis based on data uncensored for transfusion were conducted. For other secondary end points, a supportive analysis in the mITT set was performed.

The number of packed RBC units transfused in the ITT set was summarized using descriptive statistics, and 2 supporting analyses were performed to account for subjects who withdrew during the randomized controlled period before week 16. The first supportive analysis assessed the end point using log-incidence density ratios (nonparametric) adjusted for treatment. The second supportive analysis estimated the number of units of packed RBCs based on the time the patients were in the randomized controlled period (i.e., number per week multiplied by duration of end point).

Analysis Populations

• ITT set: included all randomized patients and was analyzed by treatment assignment.

• mITT set: included all randomized patients who received at least 1 dose of monotherapy study drug beyond week 4 of the randomized controlled period and was analyzed by treatment assignment.

• PP set: included all randomized patients who did not violate any inclusion or exclusion criteria and/or deviate from the protocol in a way that could influence efficacy assessment. Protocol deviations and their classifications were subject to an independent blinded review before database lock. The analysis was based on the treatment assignment.

• Completer set: included all randomized patients who had completed the week-16 efficacy assessment and was analyzed by treatment assignment.

• Safety set: included all randomized patients who received at least 1 dose of monotherapy study drug and the analysis was based upon the actual treatment received.

Results

Patient Disposition

A summary of patient disposition in the randomized controlled period of the PEGASUS trial is shown in Table 10. Of 102 screened patients, 21 (19.6%) did not meet the eligibility criteria and did not move past the screening stage and 1 patient met the eligibility criteria but did not enter any additional study periods. It is unclear which eligibility criteria contributed to the screen failure. The ITT set, mITT set, and safety set included 80 patients who were randomized to the pegcetacoplan arm (n = 41) and the eculizumab arm (n = 39) in the randomized controlled period. In the pegcetacoplan arm, 3 (7.3%) patients were discontinued from study treatment due to an AE, 1 of whom (2.4%) was also discontinued from the study. No patient was discontinued from study treatment or the study in the eculizumab arm.

Nine patients were excluded from the PP set (5 in the pegcetacoplan arm and 4 in the eculizumab arm) due to major protocol deviations (1 in the pegcetacoplan arm due to a violation of the inclusion criterion related to ARC, 1 in the pegcetacoplan arm due to missing week-16 visit, and 2 in the eculizumab arm due to receiving a transfusion despite Hb being above 9 g/dL), laboratory discrepancies between the local and central labs (2 in the eculizumab arm), or study drug discontinuation before week 16 (3 in the pegcetacoplan arm).

Table 10: Patient Disposition in the PEGASUS Trial — Randomized Controlled Period

ITT = intention to treat; mITT = modified intention to treat; PP = per protocol.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Major Protocol Deviations

Major protocol deviations are summarized in Table 11. Major protocol deviation was reported in 73.8% of patients in the pegcetacoplan arm and 76.9% of patients in the eculizumab arm. Most major protocol deviations were related to study assessment or schedule noncompliance in both treatment arms (pegcetacoplan: 48.8%; eculizumab: 64.1%). Reasons for these deviations included missed timing for laboratory or vital signs collection, missed visits, missed vaccinations, and assessments not completed by the patient.

Major protocol deviations related to informed consent (16.3%), eligibility criteria (7.5%), prohibited concomitant medication (6.3%), study drug noncompliance (6.4%), and safety reporting (2.5%) were also reported, although no notable imbalance was identified between the treatment arms for any of these categories. The 3 patients (7.7%) with major protocol deviations due to nonadherence to protocol-specified criteria for packed RBC transfusion were all from the eculizumab arm.

One study site was closed due to noncompliance to good clinical practice standards, and patients from this site (n = 2) were not excluded in neither the ITT nor the PP set.

Exposure to Study Treatments

The mean duration of treatment in the randomized controlled period was 104.9 days (SD = 17.96 days) in the pegcetacoplan arm and 98.4 days (SD = 4.89 days) in the eculizumab arm. In the pegcetacoplan arm, 5 (12.2%) patients had an interruption in at least 1 infusion, and the mean number of infusions completed per patient was 30.4 (SD = 5.13). Dose escalation of pegcetacoplan (to 1,080 mg every third day) was required in 2 patients (4.9%). The mean treatment compliance rate was 99.9% (SD = 1.8%) in the pegcetacoplan arm and 100% (SD = 0.0) in the eculizumab arm. Treatment exposure in the randomized controlled period is summarized in Table 12.

Table 11: Major Protocol Deviations — Randomized Controlled Period (ITT)

ITT = intention to treat.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Table 12: Treatment Exposure in the PEGASUS Trial — Randomized Controlled Period (Safety Set)

NA = not applicable (infusion for eculizumab was not evaluated as to whether it was completed or not); SD = standard deviation.

^aCompliance rate = total number of study infusions taken from day 1 to end of randomized controlled period (week 16) / total number of expected infusions to end of the randomized controlled period, where total numbers of expected infusions are calculated as treatment duration (days) / 7 × 2.5 for pegcetacoplan; treatment duration (days) / 7 × 2 for eculizumab.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Efficacy

Only those efficacy outcomes identified in the review protocol are reported here. Refer to Appendix 3 for detailed efficacy data.

Survival

Survival was not measured as an efficacy end point in this study. Refer to the Harms section for analysis on death events.

Hb Level

Hb outcomes in the ITT set (primary analysis) are summarized in Table 13.

Change From Baseline in Hb Level

A plot of LS mean change from baseline in Hb over time (censored for transfusion) in the randomized controlled period (ITT set) is shown in Figure 3. In the primary analysis, the LS mean change from baseline at week 16 in Hb level (primary end point) was 2.37 g/dL (SE = 0.36 g/dL) in the pegcetacoplan arm and –1.47 g/dL (SE = 0.67 g/dL) in the eculizumab arm, with a between-group difference in LS means of 3.84 g/dL (95% CI, 2.33 to 5.34 g/dL) in favour of pegcetacoplan (P < 0.0001). Results of the sensitivity analyses (controlled-based pattern imputation and tipping point analyses) and supportive analysis using all patient data (uncensored for transfusion; Table 39 in Appendix 3) were also consistent with the primary analysis.

Hb Response and Normalization in the Absence of Transfusion

Hb response (i.e., an increase of at least 1 g/dL from baseline) and Hb normalization in the absence of transfusion at week 16 were secondary end points. Hb response in the absence of transfusion was achieved in 75.6% of patients in the pegcetacoplan arm and by no patients in the eculizumab arm, with an adjusted risk difference of 67.5% (95% CI, 54.5% to 80.4%). Hb normalization in the absence of transfusion was achieved in 34.1% of patients in the pegcetacoplan arm and 0% of patients in the eculizumab arm, with an adjusted risk difference of 30.4% (95% CI, 14.9% to 45.9%). Results based on data uncensored for transfusion were the same (Table 39).

Table 13: Hb Outcomes in the PEGASUS Trial — Randomized Controlled Period (ITT; Censored for Transfusion)

CI = confidence interval; Hb = hemoglobin; ITT = intention to treat; LS = least squares; SD = standard deviation; SE = standard error.

^aBaseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

^bThe analysis was conducted using a MMRM, with change from baseline at week 16 in Hb level as the dependent variable. The model was adjusted for treatment group, study visit, number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³), the study visit by treatment group interaction, and baseline Hb level (continuous).

^cThe significance threshold was set at a 2-sided alpha of 0.05.

^dHb response was defined as an increase of at least 1 g/dL in Hb from baseline, excluding data before the Randomized Controlled Period.

^eThe risk difference and 95% CI were constructed using the stratified Miettinen-Nurminen method. This end point was not included in the statistical testing hierarchy.

^fHb normalization was defined as a Hb level at or above the lower limit of the normal range.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Figure 3: LS Mean Change From Baseline in Hb Over Time in the PEGASUS Trial — Randomized Controlled Period (ITT; Censored for Transfusion)

APL-2 = pegcetacoplan; Hb = hemoglobin; ITT = intention to treat; LS = least squares.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Transfusion

Transfusion avoidance and the number of packed RBC units transfused analyses in the ITT set (primary analysis) are summarized in Table 14.

Transfusion Avoidance

Transfusion avoidance (i.e., the proportion of patients who did not require a transfusion) during the randomized controlled period was a key secondary end point and is summarized in Table 14. The end point was tested for noninferiority according to the hierarchical testing procedure. In the primary analysis (ITT), the adjusted risk difference in transfusion avoidance between the pegcetacoplan and eculizumab arms was 62.5% (95% CI, 48.3% to 76.8%). Results of the supportive analyses were consistent with the primary analysis (PP analysis shown in Table 38 in Appendix 3). The lower bound of the 95% CI of risk difference was greater than the NIM of –20% in both ITT and PP analysis sets, supporting noninferiority between treatment groups in transfusion avoidance.

Number of Packed RBC Units Transfused

As summarized in Table 14, the mean number of packed RBC units transfused during the randomized controlled period (secondary end point) was 0.6 units (SD = 2.03 units) in the pegcetacoplan arm and 5.1 units (SD = 5.6 units) in the eculizumab arm in both the primary ITT analysis and the supportive mITT analysis.

Table 14: Tranfusion Outcomes in the PEGASUS Trial — Randomized Controlled Period (ITT)

CI = confidence interval; ITT = intention to treat; RBC = red blood cell; SD = standard deviation.

^aTransfusion avoidance was defined as the proportion of patients who did not require a transfusion during the randomized controlled period.

^bPatients who did not have a transfusion but withdrew before week 16 were considered to have had a transfusion.

^cThe risk difference and 95% CI were constructed using the stratified Miettinen-Nurminen method.

^dThe P value was based on Cochran-Mantel-Haenszel chi-square test stratified by the number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4) and the platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³). In accordance with the hierarchal testing procedure, noninferiority but not superiority testing was conducted.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Thrombotic Event

Thrombotic event was not measured as an efficacy end point in this study. Refer to the Harms section for analysis on thrombotic events.

Symptoms of PNH

FACIT-Fatigue Scale

Change from baseline at week 16 in FACIT-Fatigue score was a key secondary end point. A higher FACIT-Fatigue score indicates less fatigue. As shown in Table 15, the LS mean change from baseline at week 16 in FACIT-Fatigue score in the ITT set (censored for transfusion) was 9.22 points (SE = 1.61 points) in the pegcetacoplan arm and –2.65 points (SE = 2.82 points) in the eculizumab arm, with a between-group difference in LS mean of 11.87 points (95% CI, 5.49 to 18.25 points). Results of the supportive analyses were consistent with the primary ITT analysis (PP analysis shown in Table 38; analysis based on data uncensored for transfusion in Table 39 in Appendix 3).

An additional responder analysis was performed to assess the proportion of patients with at least a 3-point increase in FACIT-Fatigue score from baseline at week 16 (censored for transfusion), and the proportion was 73.2% in the pegcetacoplan arm and 0% in the eculizumab arm.

Table 15: FACIT-Fatigue Score Outcomes in the PEGASUS Trial — Randomized Controlled Period (ITT; Censored for Transfusion)

CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy; ITT = intention to treat; LS = least square; SD = standard deviation; SE = standard error.

^aBaseline was defined as the last available nonmissing observation before the first dose of pegcetacoplan.

^bThe analysis was conducted using a MMRM, with change from baseline at week 16 in FACIT-Fatigue score as the dependent variable. The model was adjusted for treatment group, study visit, number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³), the study visit by treatment group interaction, and baseline FACIT-Fatigue score (continuous).

^cIn accordance with the hierarchal testing procedure, noninferiority and superiority testing was not conducted.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

HRQoL or QoL

LASA

As shown in Table 16, the LS mean change from baseline at week 16 in LASA score (secondary end point, censored for transfusion) was 49.4 points (SE = 10.2 points) in the pegcetacoplan arm and –9.7 points (SE = 19.0 points) in the eculizumab arm, with a between-group difference of 59.1 points (95% CI, 16.9 to 101.3 points). Results of the supportive mITT analysis (censored for transfusion) were consistent with the primary analysis.

Table 16: Change From Baseline at Week 16 in LASA Score in the PEGASUS Trial — Randomized Controlled Period (ITT; Censored for Transfusion)

CI = confidence interval; ITT = intention to treat; LASA = Linear Analogue Scale Assessment; LS = least squares; SD = standard deviation; SE = standard error.

^aBaseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

^bThe analysis was conducted using a MMRM, with the change from baseline to 16 weeks in LASA score as the dependent variable. The model was adjusted for treatment group, study visit, number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³), the study visit by treatment group interaction, and baseline LASA score (continuous).

^cThis end point was not adjusted for multiplicity.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

EORTC QLQ-C30

Change from baseline at week 16 in the global health status/QoL scale score, and select symptom subscales relevant to PNH (i.e., fatigue, pain, and dyspnea) are summarized in Table 17. The results for other subscales are summarized in Table 40 in Appendix 3.

The LS mean difference in change from baseline at week 16 in global health status score between pegcetacoplan and eculizumab was 18.62 (95%CI, 0.12 to 37.13) points. The difference in LS mean change in score from baseline at week 16 between pegcetacoplan and eculizumab with respect to fatigue, pain, and dyspnea was –20.74 (95% CI, –35.29 to –6.19) points, –2.76 (95% CI, –20.36 to 14.85) points, and –14.57 (95% CI, –29.90 to 0.76) points, respectively.

Breakthrough Hemolysis

Breakthrough hemolysis was not assessed in the efficacy analysis. Refer to the Harms section for data on hemolysis.

Complications of PNH

Complications of PNH were not assessed in the efficacy analysis. Refer to the Harms section for data on complications of PNH.

Intravascular Hemolysis

Change From Baseline in LDH Level

As summarized in Table 18, the LS mean change from baseline in LDH level at week 16 (key secondary end point) in the ITT set (censored for transfusion) was –14.8 U/L (SE = 42.7 U/L) in the pegcetacoplan arm and –10.1 U/L (SE = 71.0 U/L) in the eculizumab arm. The between-group difference in LS means was –4.6 U/L (95% CI, –181.3 to 172.0 U/L). Noninferiority was not met because the upper bound of the 95% CI of the between-group difference was not less than the NIM of 20 U/L in both the ITT and PP sets (PP analysis in Table 38 in Appendix 3). Results of a supportive analysis based on data uncensored for transfusion (Table 39 in Appendix 4) were consistent with the primary analysis. Change from baseline in LDH level was the third secondary outcome in the statistical testing hierarchy for noninferiority, and no further testing was conducted.

An additional LDH normalization analysis was conducted to assess the proportion of patients who achieved LDH normalization (i.e., LDH level at or below ULN at week 16) in the absence of transfusion (during the randomized controlled period). The proportion was 70.7% in the pegcetacoplan arm and 15.4% in the eculizumab arm, with a risk difference of 48.8% (95% CI, 32.3% to 65.3%). In the analysis based on data uncensored for transfusion (Table 39), LDH normalization was achieved in 73.2% of patients in the pegcetacoplan arm and 59.0% of patients in the eculizumab arm, with a risk difference of 12.3% (95% CI, –7.0% to 31.5%).

Table 18: LDH Outcomes in the PEGASUS Trial — Randomized Controlled Period (ITT; Censored for Transfusion)

CI = confidence interval; ITT = intention to treat; LDH = lactate dehydrogenase; LS = least squares; SD = standard deviation; SE = standard error.

^aBaseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

^bThe analysis was conducted using a MMRM, with change from baseline at week 16 in LDH level as the dependent variable. The model was adjusted for treatment group, study visit, number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³), the study visit by treatment group interaction, and baseline LDH level (continuous).

^cIn accordance with the hierarchal testing procedure, noninferiority but not superiority testing was conducted.

^dThe normal range of LDH is 113 to 226 U/L.

^eThe risk difference and 95% CI were constructed using the stratified Miettinen-Nurminen method.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Extravascular Hemolysis

A summary of reticulocyte, indirect bilirubin, and haptoglobin outcomes is provided in Table 19.

Reticulocyte Outcomes

The change from baseline in ARC at week 16 (censored for transfusion) was a key secondary end point and was tested for noninferiority according to the hierarchical testing procedure. The LS mean change from baseline in ARC at week 16 in the ITT set (censored for transfusion) was –135.8 × 10⁹ cells/L (SE = 6.5 × 10⁹ cells/L) in the pegcetacoplan arm and 27.9 × 10⁹ cells/L (SE = 11.9 × 10⁹ cells/L) in the eculizumab arm, with a between-group adjusted mean difference of –163.6 × 10⁹ cells/L (95% CI, –189.9 to –137.3 × 10⁹ cells/L). Noninferiority was met because the upper bound of the 95% CI of the adjusted mean difference was less than the prespecified the NIM of 10 × 10⁹ cells/L in the ITT and PP sets (PP analysis in Table 38 in Appendix 3). Results of a supportive analysis based on data uncensored for transfusion (Table 39 in Appendix 3) were also consistent with the primary analysis.

Reticulocyte normalization in the absence of transfusions at week 16, a secondary end point, was achieved in 78.0% of patients in the pegcetacoplan arm and 2.6% of patients in the eculizumab arm, with a risk difference of 66.4% (95% CI, 53.1% to 79.7%). In the analysis based on data uncensored for transfusion (Table 39), ARC normalization was achieved in 80.5% of patients in the pegcetacoplan arm and 17.9% of patients in the eculizumab arm, with a risk difference of 54.8% (95% CI, 38.8% to 70.7%).

Indirect Bilirubin and Haptoglobin

The LS mean change from baseline in indirect bilirubin level at week 16 (secondary end point) in the ITT set (censored for transfusion) was –17.8 µmol/L (SE = 2.3 µmol/L) in the pegcetacoplan arm and 4.15 µmol/L (SE = 4.48 µmol/L) in the eculizumab arm, with a between-group difference of –21.9 µmol/L (95% CI, –32.5 to –11.4 µmol/L).

The LS mean change from baseline in haptoglobin level at week 16 (secondary end point) in the ITT set (censored for transfusion) was –0.02 g/L (SE = 0.03 g/L) in the pegcetacoplan arm and 0.12 g/L (SE = 0.06 g/L) in the eculizumab arm, with a between-group difference of –0.14 g/L (–0.28 to –0.01 g/L).

Table 19: Reticulocyte, Indirect Bilirubin, and Haptoglobin Outcomes in the PEGASUS Trial — Randomized Controlled Period (ITT; Censored for Transfusion)

ARC = absolute reticulocyte count; CI = confidence interval; ITT = intention to treat; LS = least squares; SD = standard deviation; SE = standard error.

^aBaseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

^bThe analysis was conducted using a MMRM. The model was adjusted for treatment group, study visit, number of packed RBC transfusions in the previous 12 months (< 4 vs. ≥ 4), platelet count at screening (< 100,000/mm³ vs. ≥ 100,000/mm³), the study visit by treatment group interaction, and their own baseline level (continuous).

^cIn accordance with the hierarchal testing procedure, noninferiority but not superiority testing was conducted.

^dReticulocyte normalization was defined as a reticulocyte count below the ULN (i.e., 120 × 10⁹ cells/L).

^eThe risk difference and 95% CI were constructed using the stratified Miettinen-Nurminen method.

^fThis end point was not included in the statistical testing hierarchy.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Health Care Resource Utilization

Health care resource utilization was not measured in this study.

Harms

Only those harms identified in the review protocol are reported here. Refer to Table 20 for detailed harms data in the randomized controlled period.

Table 20: Summary of Harms in the PEGASUS Trial — Randomized Controlled Period (Safety Set)

TEAE = treatment-emergent adverse event.

Note: A TEAE was defined as an AE that commenced on or after the first study drug administration or an AE that increased in severity after pre-treatment.

^aFrequency > 10%.

^bOccurred in ≥ 2 patients.

^cOccurred in ≥ 3 patients.

Source: PEGASUS Clinical Study Report (16 weeks).⁶

Run-In Period

During the run-in period (when both pegcetacoplan and eculizumab were used concurrently for 4 weeks), TEAEs were reported in 69 patients (86.3%), but none led to death, discontinuation of the study treatment or the study. The most common TEAEs were injection site erythema (38.8%), injection site pruritus (13.8%), and headache (12.5%), none of which was serious. A serious TEAE was reported in 1 patient due to sepsis and was considered related to both pegcetacoplan and eculizumab. This serious TEAE was resolved during the run-in period despite continued treatment with both pegcetacoplan and eculizumab. This patient was later randomly assigned to pegcetacoplan and had no subsequent TEAEs related to infection.

Randomized Controlled Period

Adverse Events

During the randomized controlled period, TEAEs were reported in 87.8% and 87.2% of patients in the pegcetacoplan arm and the eculizumab arm, respectively. The most common TEAEs (in at least 10% of patients) with pegcetacoplan treatment included diarrhea, injection site erythema, injection site reaction, and abdominal pain, all of which were more commonly reported in the pegcetacoplan arm than the eculizumab arm. The incidence of breakthrough hemolysis (9.8%), headache (7.3%), fatigue (4.9%), dizziness (2.4%), backpain (7.3%), and anemia (0% were numerically lower in the pegcetacoplan arm than the eculizumab arm (hemolysis and headache: 23.1%; fatigue: 15.4%; dizziness and backpain: 10.3%; anemia: 12.8%).

Serious Adverse Events

Serious TEAEs were reported in 7 (17.1%) patients in the pegcetacoplan arm, with the most common event being hemolysis, reported in 2 patients. Serious TEAEs were reported in 6 (15.4%) patients in the eculizumab arm, with the most common event being anemia (reported in 2 patients).

Withdrawals Due to TEAE

Three (7.3%) patients in the pegcetacoplan arm discontinued treatment due to a TEAE, all as a result of breakthrough hemolysis. No patient in the eculizumab arm discontinued treatment due to a TEAE.

Mortality

No death was reported in either treatment arm of the study.

Notable Harms

Serious bacterial infections: Serious treatment-emergent bacterial infection was reported in 1 (2.4%) patient in the pegcetacoplan and none of the patients in the eculizumab arm. No serious infections in the study were known to be caused by an encapsulated organism.

Infusion-related reaction: A notably higher incidence of injection site–related TEAEs was reported in the pegcetacoplan arm (36.6%) than the eculizumab arm (2.6%), with the most common events (≥ 5%) in the pegcetacoplan arm being injection site erythema (17.1%), reaction (12.2%), swelling (9.8%), and induration (7.3%).

Immunogenicity: No patient in the pegcetacoplan arm and 2 patients in the eculizumab arm had a positive antipegcetacoplan peptide antibody response.

Thrombosis: There was no report of thrombosis in either treatment arm.

Pulmonary hypertension: There was no report of pulmonary hypertension in either treatment arm.

Chronic kidney disease: There was no report of chronic kidney disease in either treatment arm.

Hemolysis: Breakthrough hemolysis was reported in 4 (9.8%) patients in the pegcetacoplan arm and in 9 (23.1%) patients in the eculizumab arm.

Critical Appraisal

Internal Validity

The PEGASUS trial was a phase III, randomized, open-label, active-controlled trial. The methods of randomization, which involved stratification by the number of RBC transfusions in the previous 12 months and platelet count and concealment of the randomized assignment with interactive response technology, were appropriate. There was no notable difference between treatment arms for most baseline characteristics. The pegcetacoplan arm had a shorter mean time since diagnosis, a lower mean LDH level, and a higher proportion of patients with a history of thrombosis and a higher proportion of patients receiving eculizumab at an increased dose at baseline than in the eculizumab arm, although the clinical experts consulted by CADTH commented that these differences were unlikely to have confounded the study results.

The open-label study design was reasonable, given the distinct routes and frequency of administration of the 2 interventions, which could allow investigators and patients to make inferences about treatment assignment, regardless of blinding. However, reporting of FACIT-Fatigue, LASA, and EORTC QLQ-C30 outcomes was prone to bias in favour of pegcetacoplan, given the subjective nature of these outcomes, although the extent of bias is unclear. Reporting of AEs could also have been biased due to the open-label study design, with potential for bias in favour of eculizumab. In addition, a high number of major protocol deviations related to study assessment or schedule noncompliance (54.3%), (e.g., missed timing for laboratory or vital signs collection, missed visits, assessment incomplete by patient) was reported; these were more common in the eculizumab arm (64.1%) than the pegcetacoplan arm (48.8%). Nonetheless, all major protocol deviations that were judged to have influenced efficacy assessment were excluded from the PP set.

Transfusion was allowed in patients with Hb levels lower than 9 g/dL if symptoms were present. Because symptom evaluation is subjective, transfusion decisions could be influenced by knowledge of treatment assignment, leading to potential bias in favour of pegcetacoplan. Transfusion was allowed at the discretion of the investigators in 2 patients in the eculizumab arm who did not meet the predefined clinical criteria. Considering that an independent blinded review of these protocol deviations took place before the database lock, the incidence of deviations was small, and such deviations were excluded from the PP set, the concern for bias is small.

Prior to the randomized controlled period, patients received pegcetacoplan and eculizumab concurrently to avoid insufficient complement inhibition in the 4-week run-in period. The clinical experts commented that the interventions administered during the run-in period would not influence the primary efficacy assessment at week 16, given than the drugs require frequent dosing (every 2 weeks for eculizumab, twice weekly for pegcetacoplan) and would have been completely washed out by week 16.

The statistical analyses were generally well designed. The study was powered to detect a treatment difference in the primary end point between treatment arms in the ITT population and the enrolled sample size was adequate. A hierarchical testing procedure was appropriately used to account for multiplicity in all key secondary efficacy end points. No formal hypothesis testing was conducted for categorical secondary efficacy outcomes (Hb normalization, Hb response, reticulocyte normalization) or for number of packed RBCs transfused. The statistical testing for HRQoL outcomes (LASA, EORTC QLQ-C30 scores), indirect bilirubin, and haptoglobin were associated with an increased risk of type I error due to lack of control for multiplicity. No conclusion can be made about subgroup effects because the subgroups of interest related to disease activity were not addressed in the submission.

The sponsor assumed a treatment difference of 1 g/dL between pegcetacoplan and eculizumab in the sample size calculation, as informed by PNH experts. The clinical experts consulted by CADTH considered an improvement of 2 g/dL to be highly favourable; however, an improvement of at least 1 g/dL was considered reasonable and is expected to result in a clinically meaningful improvement in most patients with PNH, especially those with severe anemia at baseline. It has been proposed that Hb level is a strong surrogate biomarker for clinical benefits in patients with sickle cell disease receiving stem cell or gene therapy;^24,25 however, evidence in patients with PNH is scarce due to the rarity of the disease. Justification for NIMs of the FACIT-Fatigue Scale, ARC, LDH level, and transfusion avoidance were not available from the sponsor due to the scarcity of information on comparable patient populations at the start of the trial. A recent study using registry data suggested the use of 5 points as a clinically important difference for the FACIT-Fatigue Scale for in PNH patients;²⁷ however, the study examined a treatment-naive population that does not fully align with the patient population of interest to this review (treatment-experienced), and it is also unclear if the identified value was a MID. Nonetheless, the chosen NIM of 3 points would be considered conservative for the FACIT-Fatigue Scale. The clinical experts consulted by CADTH noted that the NIMs for transfusion avoidance and LDH level were reasonable.

For a conservative approach, it is generally preferred that the claim of noninferiority be based on agreement between the ITT and PP populations. PP analyses were conducted as supportive analyses in the trial. For the key secondary outcomes that were tested for noninferiority (i.e., transfusion avoidance, change from baseline at week 16 in ARC, change from baseline at week 16 in LDH level), results in the supportive PP analyses were consistent with those in the primary ITT analyses.

Bias due to study drop-outs is unlikely, given the low incidence of study discontinuation in both treatment arms (pegcetacoplan: 2.4%; eculizumab: 0%) at week 16. Missing data were found to be at least 10% in the pegcetacoplan arm and at least 85% in the eculizumab arm for all efficacy outcomes, which was largely due to data censoring after a transfusion event. Missing data for continuous outcomes were implicitly imputed by MMRM, which relies on the assumption that data are missing at random. This assumption is unlikely to hold for Hb outcomes because missingness was related to censoring for transfusion and transfusion need was dependent on Hb level. The study conducted sensitivity analyses (the control-based pattern imputation method and a tipping point analysis) that used imputation methods based on the missingness-not-at-random assumption for the primary end point, as well as a supportive analysis that assesses all patient data (i.e., no censoring for transfusion) for the primary and all key secondary efficacy end points. Results of these supportive and sensitivity analyses align with the primary analysis, increasing the certainty of the findings. However, the clinical experts indicated that LDH level is independent of transfusion. An agreement between the primary LDH analysis (censored for transfusion) and the additional analysis uncensored for transfusion was observed, providing reassurance for this outcome.

The validity, reliability, and responsiveness of the patient-reported outcome instruments (EORTC QLQ-C30, FACIT-Fatigue, LASA) have not been characterized in patients with PNH previously, aside from 1 study showing evidence of content validity for the EORTC QLQ-C30 and FACIT-Fatigue Scale in this patient population.²⁶ In addition, MID estimates for PNH have not been established for these instruments.

External Validity

According to the clinical experts consulted by CADTH, the inclusion and exclusion criteria, in general, align with selection criteria that would be adopted by most clinicians when identifying suitable candidates for pegcetacoplan. The clinical experts commented that the inclusion of patients with an Hb level of 10.5 g/dL was consistent with the criteria used by most clinicians in clinical practice, although they recognized that there may be variability in the cut-offs used by other clinicians. The clinical experts noted most patients would not be switched to pegcetacoplan immediately after receiving a stable dose of eculizumab for 3 months, as it would generally take at least 6 months to ascertain the underlying cause of treatment failure; however, the concern is likely minimal because most patients appeared to have a long history of eculizumab treatment at baseline. In addition, patients with certain cardiovascular diseases and those receiving QT-prolonging medications were excluded from the study, which the clinical experts noted was reasonable and could be due to safety concerns, although there are rarely QT-related issues with complement inhibitors in their experience. Patients with intolerance to C5 inhibitors were also not included, although the impact on generalizability is expected to be small, as such patients are uncommon, per the clinical experts. The baseline characteristics of the study population were generally reflective of the population with PNH in Canada, according to the clinical experts.

The dosing, criteria for dose escalation, and administration of pegcetacoplan in the study were consistent with the product monograph. The clinical experts considered eculizumab to be an appropriate comparator, as it is a standard of care and is prescribed for most patients with PNH in clinical practice. Patients in the eculizumab arm received treatment based on their dose established before the study. The clinical experts commented that the distribution of eculizumab dosing in the study population aligns with clinical practice, with approximately 20% to 30% of patients receiving higher or more frequent doses than the standard recommended dosage. In the study, transfusion was provided according to prespecified criteria based on Hb levels and the presence of symptoms. The clinical experts noted the transfusion criteria were consistent with the criteria used in clinical practice.

The efficacy outcomes measured in the study were of clinical importance to both patients and clinicians. The clinical experts and patient group input both noted that improvements in Hb level and QoL and reductions in hemolysis, symptoms, and transfusion needs were the key goals of treatment for PNH, and all were measured in the trial. The clinical experts noted that the duration of follow-up (16 weeks) was adequate for assessing these outcomes; however, for other important outcomes, such as breakthrough hemolysis, survival, thrombosis, and other complications of PNH, a longer follow-up, of at least 2 years, would be required to gain certainty in the results. The clinical relevance of patient-reported outcome instruments (FACIT-Fatigue, EORTC QLQ-C30, LASA) is uncertain because they are not routinely administered in clinical practice, per the clinical experts. Nevertheless, these scales have captured some of the common symptoms of PNH (e.g., fatigue, pain, dyspnea) reported by patients and would be considered relevant in the assessment of pegcetacoplan.

It should be noted that this trial is the only phase III study to provide direct comparative evidence between pegcetacoplan and a C5 inhibitor. The absence of head-to-head evidence comparing pegcetacoplan and ravulizumab in patients with an inadequate response to ravulizumab represents an evidence gap in the management of PNH.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

In the absence of a head-to-head comparison between pegcetacoplan and ravulizumab, CADTH conducted a literature review to identify indirect treatment comparisons (ITCs) that could supplement the available direct evidence from the PEGASUS trial in addition to the sponsor’s submitted ITC. A focused literature search for ITCs mentioning PNH, pegcetacoplan, ravulizumab, or eculizumab was conducted in MEDLINE All, with no limits applied to search results. Titles, abstracts, and full-text articles were screened for inclusion by 2 reviewers based on the review criteria outlined in Table 5. Of the 2 potentially relevant ITCs identified by the search, 1 was a duplicate of the sponsor-submitted ITC and the other did not include pegcetacoplan. In total, 1 sponsor-submitted ITC,⁷ which was used to inform the pharmacoeconomic model, was summarized and critically appraised.

Description of Indirect Comparison

The sponsor submitted an anchored MAIC to evaluate the relative efficacy of pegcetacoplan to ravulizumab in adult patients with PNH previously treated with eculizumab. The MAIC did not report a systematic literature review to identify relevant studies for inclusion. Two studies were included in the analysis: patient-level data from the PEGASUS study, comparing pegcetacoplan and eculizumab, and aggregate patient data from the ALXN study⁸ comparing ravulizumab and eculizumab. Outcomes analyzed were transfusion avoidance, number of packed RBCs transfused, Hb level stabilization, change from baseline in LDH level, LDH level normalization, fatigue and fatigue symptoms, global health status, and physical functioning.

Methods of MAIC

Objectives

The objective of the sponsor’s MAIC was to assess the comparative efficacy of pegcetacoplan and ravulizumab in adult patients with PNH previously treated with eculizumab.

Study Selection Methods

The authors did not report a literature search or describe their methods for data extraction or quality assessment of the 2 included studies. The outcomes and their corresponding time of assessment from the 2 studies are summarized in Table 13. Definitions for clinical, hematological, fatigue, and QoL outcomes were similar in the PEGASUS and ALXN studies.

Table 21: Comparison of Study Outcomes in the PEGASUS and ALXN Studies

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT = Functional Assessment of Chronic Illness Therapy; Hb = hemoglobin; LDH = lactate dehydrogenase; RBC = red blood cell; ULN = upper limit of normal.

^aLDH level normalization is defined as the proportion of patients who achieved an LDH level ≤ 1 × ULN (226 U/L) in the absence of transfusions from baseline through the end of follow-up.

^bLDH level normalization is defined as the proportion of patients who achieved an LDH level ≤ 1 × ULN (246 U/L), with or without transfusions (i.e., patients were not excluded if they received transfusions during follow-up).

Source: Sponsor-submitted ITC.⁷

MAIC Analysis Methods

The authors used an anchored MAIC by combining individual patient data from the PEGASUS trial and aggregate data from the ALXN trial to compare pegcetacoplan to ravulizumab anchored to the common comparator eculizumab. Baseline demographic and clinical characteristics were summarized using frequencies and percentages for categorical variables and means and SDs for continuous variables before and after matching procedures. Baseline characteristics were classified as an effect modifier, a purely prognostic variable, or neither, based on clinical input regarding biological plausibility. Classification of variables by type of outcome are provided in Table 22.

Table 22: Classification of Variables by Type of Outcome

LDH = lactate dehydrogenase.

^aOutcomes include transfusion avoidance, transfusion requirements, Hb level, and hemoglobin stabilization.

^bOutcomes include LDH level (percent change and change from baseline), LDH normalization, and breakthrough hemolysis.

^cOutcomes include fatigue (FACIT-Fatigue Scale), general health status (EORTC QLQ-C30), physical functioning (EORTC QLQ-C30), and fatigue symptoms (EORTC QLQ-C30).

Source: Sponsor-submitted ITC.⁷

A propensity score model using logistic regression was used to estimate the likelihood of enrolment in the ALXN study versus the PEGASUS study. The logistic regression model was estimated using the method of moments. Weights were assigned such that the weighted means and proportions of baseline characteristics in the PEGASUS study exactly matched those reported in the ALXN study. The weight of each patient enrolled in the PEGASUS study was equal to the inverse odds of their enrolment in the ALXN study versus the PEGASUS study. Model adequacy was assessed with visual inspection of histograms of patient weights and effective sample size (ESS). Models that retained at least 50% of the initial PEGASUS population while adjusting for effect modifiers were selected. The distribution of baseline demographic and clinical characteristics was compared across patient groups before and after matching. Comparisons of clinical and hematological outcomes with fatigue and QoL outcomes were adjusted for separate baseline characteristics. Before matching, Wald tests and 95% CIs were used to compare categorical and continuous outcomes (i.e., chi square distribution and z score, respectively). After matching, outcomes were compared between balanced treatment groups using weighted Wald tests with 95% CIs that incorporated weights generated during matching.

Anchored comparisons based on the unweighted sample before matching and unanchored comparisons (i.e., excluded data for patients randomized to eculizumab) were conducted as sensitivity analyses. All effect modifiers, whether balanced or imbalanced at baseline between the PEGASUS and ALXN studies and all prognostic variables were included as matching variables. In addition, a sensitivity analysis was conducted by revising the definition of LDH level normalization in the PEGASUS study to match that in the ALXN study, which meant that patients who received a transfusion during follow-up were not excluded from the measurement of LDH level normalization.

Results of MAIC

Summary of Included Studies

Study characteristics of the PEGASUS and ALXN studies are summarized in the Table 23.

The patients included in the MAIC were 18 years or older, previously treated with eculizumab (for at least 3 months in the PEGASUS study and for at least 6 months in the ALXN study), received meningococcal vaccination, had an absolute neutrophil count greater than 500/mm³ at screening, had an adequate platelet count at screening (greater than 50,000/mm³ in the PEGASUS study and greater than 30,000/mm³ in the ALXN study), and did not have a history of bone marrow transplant. The following criteria were not included in the ALXN study: Hb level less than 10.5 g/dL and ARC greater than 1 times the ULN at screening. The individual patient data from the PEGASUS study were reanalyzed, and patients with an LDH level of 1.5 times the ULN or less at screening and without major adverse vascular events in the 6 months before treatment were selected to align more closely with the patients enrolled in the ALXN study. After implementing these 2 criteria, the ESSs for the pegcetacoplan and eculizumab groups were 36 (87.8% of the original sample size) and 32 patients (82.1% of the original sample size), respectively. Five patients in the pegcetacoplan group and 7 patients in the eculizumab group were excluded in the analysis because their LDH was greater than 1.5 times the ULN at screening. No patients in the PEGASUS study had a major adverse vascular event in the 6-month period before treatment. In the ALXN study, 97 patients in the ravulizumab group and 98 patients in the eculizumab group were included in the analysis.

The baseline characteristics of patients before and after matching are summarized in Table 24. Prior to matching, the distribution of effect modifiers, including patient age, race (white, African American, and other or multiple races), weight, history of aplastic anemia, and LDH level, was similar for patients randomized to receive pegcetacoplan in the PEGASUS study and those randomized to receive ravulizumab in the ALXN study. There were fewer patients of Asian race in the pegcetacoplan group than in the ravulizumab group (13.9% versus 23.7%). Compared with patients who received ravulizumab, a greater proportion of pegcetacoplan patients were female (69.4% versus 48.5%) and had a history of transfusions in the year before the study (72.2% versus 13.4%). Mean Hb was lower for patients who received pegcetacoplan than for those who received ravulizumab (8.7 g/dL versus 11.1 g/dL).

Comparisons of clinical and hematological outcomes were adjusted for patient age at first study infusion, female sex, white race, Asian race, history of aplastic anemia, and LDH level at baseline, such that the means and proportions of these effect modifiers matched exactly for patients receiving pegcetacoplan and ravulizumab. After matching procedures, the ESS was 24 patients and 12 patients for pegcetacoplan and eculizumab, respectively. Comparisons for fatigue and QoL outcomes were adjusted for patient age at first study infusion, body weight, history of aplastic anemia, and LDH level at baseline. The authors noted that they did not match the effect modifiers of Hb level and history of transfusions due to reduced ESS and the presence of extreme patient inverse probability weights. No description was provided for the handling of different follow-up times reported in the studies (16 weeks for PEGASUS and 26 weeks for ALXN). After matching procedures, the ESS was 34 patients and 9 patients for pegcetacoplan and eculizumab, respectively.

Table 23: Summary of Study Characteristics

CABG = coronary artery bypass graft; ESS = effective sample size; LDH = lactate dehydrogenase; MAVE = major adverse vascular event; NYHA = New York Heart Association; PNH = paroxysmal nocturnal hemoglobinuria; ULN = upper limit of normal.

Source: Sponsor-submitted ITC.⁷

Table 24: Baseline Characteristics of the PEGASUS and ALXN Studies Before and After Matching — Clinical and Hematological Outcomes

ESS = effective sample size; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; SD = standard deviation.

^aAfter matching procedures, the ESS was 24 patients and 12 patients for pegcetacoplan and eculizumab, respectively.

^bIndicates variable included in matching procedures. These included age at first infusion of study drug, female, white, Asian, LDH, and history of aplastic anemia.

Source: Sponsor-submitted ITC.⁷

Table 25: Baseline Characteristics of the PEGASUS and ALXN Studies Before and After Matching — Fatigue and QoL Outcomes

ESS = effective sample size; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; QoL = quality of life; SD = standard deviation.

^aAfter matching procedures, the ESS was 34 patients and 9 patients for pegcetacoplan and eculizumab, respectively.

^bIndicates variable included in matching procedures. These included age at first infusion of study drug, weight, LDH, and history of aplastic anemia.

Source: Sponsor-submitted ITC.⁷

Results

Clinical and Hematological Outcomes

The results for clinical and hematological outcomes are presented in Figure 4. After matching and anchoring on eculizumab, treatment with pegcetacoplan compared with ravulizumab was associated with more transfusion avoidance (adjusted difference = 71.4%; 95% CI, 53.5% to 89.3%), more Hb level stabilization (adjusted difference = 75.5%; 95% CI, 56.4% to 94.6%), more LDH level normalization in the absence of transfusions (adjusted difference = 64.0%; 95% CI, 41.8% to 86.1%), and fewer mean number of units of packed RBCs transfused (adjusted difference = –5.7 units; 95% CI, –7.2 to –4.2 units). There was no difference found in the mean change from baseline in LDH levels (adjusted mean difference = 0.3 U/L; 95% CI, –154.5 U/L to 155.1 U/L), although the CI was relatively wide.

Fatigue and QoL Outcomes

The results for fatigue and QoL outcomes are presented in Figure 5. All reported fatigue and QoL outcomes favoured pegcetacoplan compared with ravulizumab. Treatment with pegcetacoplan was associated with improvements in the adjusted difference in mean change from baseline in fatigue (8.2 points; 95% CI, 3.8 to 12.6 points), global health status (9.6 points; 95% CI, 0.1 to 19.0 points), physical functioning (11.5 points; 95% CI, 3.6 to 19.5 points), and fatigue symptoms (–13.3 points; 95% CI, –23.7 to –3.0 points).

Sensitivity Analyses

The authors noted anchored comparisons based on the unweighted sample before matching and unanchored comparisons that excluded patients randomized to receive eculizumab in both studies were both consistent with the primary analysis, although the data were not reported. The authors also noted the sensitivity analysis that revised the PEGASUS definition of LDH level normalization to match the ALXN definition supported the primary analysis, such that pegcetacoplan was associated with more LDH level normalization irrespective of transfusion status (adjusted difference = 57.4%; 95% CI, 35.3% to 79.5%). The latter data were not reported in detail.

Figure 4: Anchored Comparisons of Clinical and Hematological Outcomes After Matching — PEGASUS Versus ALXN Studies

CI = confidence interval; LDH = lactate dehydrogenase.

^a Baseline characteristics were matched on age at first infusion of study drug, female, white, Asian, history of aplastic anemia, and LDH.

^b Change from baseline in LDH level was examined for week 16 for the ALXN study. During follow-up, LDH level was available at week 16 (day 113) for 94 patients who received ravulizumab and 96 patients who received eculizumab in the ALXN study.

^c In the PEGASUS study, LDH level normalization is defined as the proportion of patients who achieved an LDH level ≤ 1 × ULN (226 U/L) in the absence of transfusions from baseline through the end of follow-up. In the ALXN study, LDH level normalization is defined as the proportion of patients who achieved an LDH level ≤ 1 × ULN (246 U/L), with or without transfusions.

Source: Bhak et al. (2021).⁷ Copyright 2021 Informa UK Limited, Taylor & Francis Group. Reprinted in accordance with Creative Commons Attribution Licence CC BY-NC-ND 4.0.

Figure 5: Anchored Comparisons of Fatigue and QoL Outcomes After Matching — PEGASUS Versus ALXN Studies

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; QoL = quality of life.

^a Baseline characteristics were matched on age at first infusion of study drug, weight, history of aplastic anemia, and LDH.

^b Data were available for 67 of 68 patients in the PEGASUS study.

Source: Bhak et al. (2021).⁷ Copyright 2021 Informa UK Limited, Taylor & Francis Group. Reprinted in accordance with Creative Commons Attribution Licence CC BY-NC-ND 4.0.

Critical Appraisal of MAIC

The rationale for conducting the MAIC and its objectives were clearly reported. The authors did not report a systematic literature search, describe their methods for data extraction, or conduct quality assessment of the PEGASUS or ALXN studies. Based on CADTH’s systematic literature reviews, it’s unlikely any relevant studies were missed. The MAIC included relevant outcomes identified in the CADTH systematic review protocol, although it’s not clear if the analysis for LDH level normalization in the absence of transfusions was accurately compared across studies (in PEGASUS, LDH level normalization was assessed in the absence of transfusions, whereas in ALXN, it was assessed with or without transfusions), potentially introducing uncertainly into the estimate. Some important outcomes, such as Hb and bilirubin levels and safety, were not available for both studies in the comparison. As such, their comparative assessment remains unknown.

There were several similarities in study design, including the inclusion and exclusion criteria, across the 2 studies, which made the comparison appropriate. However, there were also several differences. The duration of follow-up for the 2 studies were different (i.e.,16 weeks for PEGASUS and 26 weeks for ALXN), which may result in the overestimation or underestimation of outcomes. The following inclusion criteria were not applied to the ALXN study: Hb level less than 10.5 g/dL and ARC greater than ULN at screening. The mean baseline Hb level was 8.7 g/dL the PEGASUS study, compared with approximately 11.0 g/dL the in ALXN study, and the difference in absolute reticulocyte counts is unknown, given that it was not reported in the ALXN study. To improve the similarity between patient samples across the 2 studies, the analysis selectively included patients from the PEGASUS study with an LDH level of 1.5 times the ULN or less at screening and without major adverse vascular events in the 6 months before treatment, reducing patient numbers. There were also differences in the treatment administration schedule, dosing regimen, and treatment modifications, and the 4-week run-in period in the PEGASUS study was not present in the ALXN study. The authors noted that these differences in study design could not be adjusted for in the analysis, which could have introduced residual confounding due unreported or unobserved cross-study differences, although the direction and extent of bias are unclear.

To account for between-study differences in patient baseline characteristics, several relevant effect modifiers were matched in the weighting process, with separate sets of variables used for clinical and hematological outcomes and fatigue and QoL outcomes. These variables were selected based on clinical input regarding biological plausibility. The clinical experts consulted by CADTH agreed that the effect modifiers used in the MAIC were reasonable, although they considered Hb level and history of transfusions as key effect modifiers. Baseline Hb levels were substantially lower in the PEGASUS study than in the ALXN study, and the proportion of patients with recent transfusion was higher in the PEGASUS study (approximately 72.0% versus approximately 12.5%). These 2 effect modifiers were not matched because they would have reduced the ESS below a preset threshold of 50% of eligible patients and because of the presence of extreme patient weights, which might have introduced unmeasurable confounding in the relative treatment effect estimates, although the direction and extent of bias are unclear. To mitigate for some of these limitations, the authors noted that sensitivity analyses using anchored comparisons based on the unweighted sample before matching and unanchored comparisons that included both effect modifiers and prognostic variables were consistent with the primary analysis.

In consideration of the strengths and limitations of the anchored MAIC, there is uncertainty about the relative treatment effect estimates favouring pegcetacoplan over ravulizumab.

Other Relevant Evidence

This section presents results from the long-term extension period of the PEGASUS trial³⁴ included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence in the systematic review.

The PEGASUS Study: Open-Label Pegcetacoplan Period

The pivotal PEGASUS trial included a 16-week primary evaluation period in which patients received randomized assignment to either pegcetacoplan or eculizumab. Presented in this section are the efficacy and safety outcomes for patients in the open-label pegcetacoplan period, up to 48 weeks after baseline. All patients, regardless of the drug received in the primary evaluation period, transitioned to pegcetacoplan for the extension period.

Methods

After the 16-week randomized controlled period, all patients who continued in the open-label pegcetacoplan period received pegcetacoplan for an additional 32 weeks. Patients who received pegcetacoplan in the randomized controlled period continued to receive pegcetacoplan monotherapy for the whole open-label pegcetacoplan period, whereas patients who received eculizumab in the randomized controlled period first entered a run-in period in which they received pegcetacoplan in addition to eculizumab for 4 weeks, and then transitioned to pegcetacoplan monotherapy for the remainder of the open-label period. All patients then had the option to continue in an ongoing long-term extension study³⁵ or a 12-week follow-up period.

Populations

All patients who entered the extension period were originally enrolled in the randomized controlled period of the PEGASUS study. As such, the inclusion and exclusion criteria are consistent with what is reported in Systematic Review section. Of the 80 patients who received pegcetacoplan or eculizumab in the randomized controlled period, 77 (96.3%) patients entered the open-label pegcetacoplan period. No notable differences in patient baseline demographics or disease characteristics were identified between the open-label period and the randomized controlled period.

Interventions

Patients either maintained their treatment with pegcetacoplan or transitioned from eculizumab to pegcetacoplan. Use of the study drug and concomitant medications was consistent with that in the randomized controlled period.

Outcomes

The change from baseline and change from week 17 to week 48 with respect to Hb level, ARC, LDH level, FACIT-Fatigue Scale score, LASA scores, EORTC QLQ-C30 scores, as well as the number of packed RBC units transfused during the open-label period (week 17 to week 48 and week 20 to week 48) were secondary end points of the PEGASUS trial. A post hoc analysis of transfusion avoidance during the 48-week study period was of interest to this review and was also summarized. Outcome definitions were consistent with those reported in the Systematic Review section.

Harms outcomes were consistent with the primary evaluation period. Briefly, TEAEs, serious TEAEs, withdrawal due to AEs, deaths, thrombotic events, laboratory parameters, and electrocardiograms were assessed.

In the open-label period, all efficacy and harms outcomes were assessed at each study visit (i.e., weeks 17, 18, 20, 22, and 24, and every 4 weeks thereafter until week 48).

Statistical Analysis

There was no comparator arm in the extension period because all patients either maintained or transitioned to treatment with pegcetacoplan. As such, there was no formal statistical testing conducted on the results. All efficacy results presented are for the ITT set of patients who entered the extension period, and descriptive statistics were used to summarize the results rather than the statistical models used in the primary evaluation period. Missing data in the extension period were not imputed. All harms results presented are for the safety set of patients who entered the extension period.

Patient Disposition

A total of 80 patients were treated with either pegcetacoplan (n = 41) or eculizumab (n = 39) in the 16-week randomized controlled period. Of these, 95.1% of patients in the pegcetacoplan arm and all patients in the eculizumab arm entered the extension period. Three patients in the pegcetacoplan to pegcetacoplan group discontinued treatment during the extension period (2 due to AEs, 1 due to physician decision) and 7 patients in the eculizumab to pegcetacoplan group discontinued treatment due to AEs.

Table 26: Patient Disposition in the PEGASUS Study — Open-Label Pegcetacoplan Period

ECU = eculizumab; ITT = intention to treat; PEG = pegcetacoplan.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Exposure to Study Treatments

In the open-label pegcetacoplan period, the mean duration of pegcetacoplan treatment was 209.8 days (SD = 39.2 days). Seven (9.1%) patients had an interruption in at least 1 pegcetacoplan infusion. The mean number of infusions completed per patient was 61.0 (SD = 12.1). Dose escalation of pegcetacoplan (to 1,080 mg every third day) was required in 15 patients (19.5%), including 2 patients who dose-escalated during the randomized controlled period. The mean treatment compliance rate was 100.8% (SD = 6.2%). Treatment exposure in the open-label pegcetacoplan period is summarized in Table 27.

Table 27: Treatment Exposure in the PEGASUS Study — Open-Label Pegcetacoplan Period (Safety Set)

ECU = eculizumab; PEG = pegcetacoplan; SD = standard deviation.

^aDose escalation of pegcetacoplan to 1,080 mg every third day.

^bCompliance rate = total number of study infusions taken / total number of expected infusions, where the total number of expected infusions was calculated as: (last dose – first dose + 3.5 days) / 7 days) × 2.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Efficacy

Survival

Survival was not measured as an efficacy end point in this study. Refer to the Harms section for analysis on death events.

Hb Level

Change in Hb Level

As summarized in Table 28, the mean change from week 17 in Hb level at week 48 (secondary end point) was –0.16 g/dL (SD = 1.15 g/dL) in the pegcetacoplan to pegcetacoplan group and 2.89 g/dL (SD = 2.08 g/dL) g/dL in the eculizumab to pegcetacoplan group. The mean change from baseline in Hb level at week 48 (secondary end point) was 2.47 g/dL (SD = 1.72 g/dL) in the pegcetacoplan to pegcetacoplan group and 2.93 g/dL (SD = 2.09 g/dL) in the eculizumab to pegcetacoplan group. The mean Hb level at each study visit over time (whole study) is shown in Figure 6.

Table 28: Change in Hb Level in the PEGASUS Study — Open-Label Pegcetacoplan Period (ITT; Uncensored for Transfusion)

ECU = eculizumab; Hb = hemoglobin; ITT = intention to treat; PEG = pegcetacoplan; SD = standard deviation.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Figure 6: Hb Level Over Time in the PEGASUS Study — Whole Study Analysis (ITT)

ALP-2 = pegcetacoplan; Hb = hemoglobin; ITT = intention to treat; LLN = lower limit of normal; SE = standard error.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan. Study periods were as follows: run-in period (baseline to day –1); randomized controlled period (day 1 to week 16); open-label pegcetacoplan period (week 17 to week 48); and follow-up period (week 49 to week 60). The eculizumab arm refers to patients who received eculizumab in the randomized controlled period and subsequently completed a 4-week run-in period (week 17 to week 20) with concurrent treatment with eculizumab and pegcetacoplan, followed by pegcetacoplan monotherapy until week 48.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Transfusion

Transfusion avoidance (post hoc) and number of packed RBC units transfused analyses are summarized in Table 29.

Transfusion Avoidance (Post Hoc Analysis)

In a post hoc analysis of transfusion avoidance, transfusion avoidance was achieved in 73.2% of patients on pegcetacoplan monotherapy (i.e., baseline to week 48) in the pegcetacoplan to pegcetacoplan group, and in 71.8% of patients on pegcetacoplan monotherapy (i.e., week 17 to week 48) in the eculizumab to pegcetacoplan group from baseline to week 48.

Number of Packed RBC Units Transfused

In the pegcetacoplan to pegcetacoplan group, the mean number of packed RBC units transfused in the open-label pegcetacoplan period (week 17 to week 48; secondary end point) was 1.79 (SD = 4.67) units. In the eculizumab to pegcetacoplan group, the mean number of packed RBC units transfused was 2.82 (SD = 8.30) units in the pegcetacoplan-only period (week 20 to 48).

Table 29: Transfusion Outcomes in the PEGASUS Study — Open-Label Pegcetacoplan Period (ITT)

ECU = eculizumab; ITT = intention to treat; NA = not applicable; PEG = pegcetacoplan; RBC = red blood cell; SD = standard deviation.

^aPatients who did not have a transfusion but withdrew before week 48 were considered to have had a transfusion. Pegcetacoplan monotherapy was given from baseline to week 48 in the pegcetacoplan to pegcetacoplan arm, and from week 17 to week 48 in the eculizumab to pegcetacoplan arm.

^bThe pegcetacoplan monotherapy period refers to week 17 to week 48 in the pegcetacoplan to pegcetacoplan arm, and week 20 to week 48 in the eculizumab to pegcetacoplan arm.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Thrombotic Event

Thrombotic events were not measured as an efficacy end point in this study. Refer to the Harms section for analysis on thrombotic events.

Symptoms of PNH

FACIT-Fatigue Scale

As summarized in Table 30, the mean change from week 17 in FACIT-Fatigue score at week 48 (secondary end point) was 1.3 points (SD = 7.8 points) in the pegcetacoplan to pegcetacoplan group and 10.2 points (SD = 11.0 points) in the eculizumab to pegcetacoplan group. The mean change from baseline in FACIT-Fatigue score at week 48 (secondary end point) was 10.1 points (SD = 9.1 points) points in the pegcetacoplan to pegcetacoplan group and 9.62 points (SD = 10.3 points) in the eculizumab to pegcetacoplan group. The mean FACIT-Fatigue score at each study visit over time is shown Figure 7.

Table 30: Change in FACIT-Fatigue Score in the PEGASUS Trial — Open-Label Pegcetacoplan Period and Whole Study Analyses (ITT; Uncensored for Transfusion)

ECU = eculizumab; FACIT = Functional Assessment of Chronic Illness Therapy; ITT = intention to treat; PEG = pegcetacoplan; SD = standard deviation.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Figure 7: FACIT-Fatigue Scale Score Over Time in the PEGASUS Trial — Whole Study Analysis (ITT)

ALP-2 = pegcetacoplan; FACIT = Functional Assessment of Chronic Illness Therapy; ITT = intention to treat; SE = standard error.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan. Study periods were as follows: run-in period (baseline to day –1); randomized controlled period (day 1 to week 16); open-label pegcetacoplan period (week 17 to week 48); and follow-up period (week 49 to week 60). The eculizumab arm refers to patients who received eculizumab in the randomized controlled period and subsequently completed a 4-week run-in period (week 17 to week 20) with concurrent treatment with eculizumab and pegcetacoplan, followed by pegcetacoplan monotherapy until week 48.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Health-Related Quality of Life

Linear Analogue Scale Assessment

As summarized in Table 31, the mean change from week 17 in LASA score at week 48 (secondary end point) was 13.1 points (SD = 46.3 points) in the pegcetacoplan to pegcetacoplan group and 62.9 points (SD = 60.1 points) in the eculizumab to pegcetacoplan group. The mean change from baseline in LASA score at week 48 (secondary end point) was 58.7 points (SD = 51.2 points) in the pegcetacoplan to pegcetacoplan group and 56.5 points (SD = 65.6 points) in the eculizumab to pegcetacoplan group. The mean change in LASA score at each study visit over time (whole study) is shown in Figure 10 in Appendix 3.

Table 31: Change in LASA Score in the PEGASUS Trial — Open-Label Pegcetacoplan Period and Whole Study Analyses (ITT; Uncensored for Transfusion)

ECU = eculizumab; ITT = intention to treat; LASA = Linear Analogue Scale Assessment; PEG = pegcetacoplan; SD = standard deviation.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

EORTC QLQ-C30

Change in EORTC QLQ-C30 (week 14 to week 48 and baseline to week 48) in the global health status/QoL score and select symptom subscales (i.e., fatigue, pain, and dyspnea) are summarized in Table 32. The mean score at each visit over time (whole study) for these scales are shown in Figure 11 (global health status/QoL), Figure 12 (fatigue), Figure 13 (pain), and Figure 14 (dyspnea).

In the pegcetacoplan to pegcetacoplan group, mean scores in the open-label period were consistent with those in the randomized controlled period for the global health status/QoL scale and all functional and symptom subscales.

In the eculizumab to pegcetacoplan group at week 48, an improvement (i.e., rise in global in health status and functioning subscale scores; decrease in symptom subscale scores) in mean score of at least 10 points from week 17 was observed for the global health status/QoL scale, as well as for the dyspnea, fatigue, physical functioning, role functioning, and social functioning subscales. For pain and for all other subscales, mean scores in the open-label period were consistent with those in the randomized controlled period.

Overall, there was no notable difference in the change from baseline mean scores at week 48 between the pegcetacoplan to pegcetacoplan group and the eculizumab to pegcetacoplan group for any EORTC QLQ-C30 subscales.

Complications of PNH

Complications of PNH were not assessed in this study.

Intravascular Hemolysis

Change From Baseline in LDH Level

As summarized in Table 33, the change from week 17 in LDH level at week 48 (secondary end point) was 8.0 U/L (SD = 129.28 U/L) in the pegcetacoplan to pegcetacoplan group and –46.84 U/L (SD = 292.61 U/L) in the eculizumab to pegcetacoplan group. The mean change from baseline in LDH level at week 48 (secondary end point) was –41.5 U/L (SD = 153.7 U/L) in the pegcetacoplan to pegcetacoplan group and –105.3 U/L (SD = 315.6 U/L) in the eculizumab to pegcetacoplan group. The change in LDH level over time (whole study) is shown in Figure 8.

Table 33: Change in LDH Level in the PEGASUS Trial — Open-Label Pegcetacoplan Period and Whole Study Analyses (ITT; Uncensored for Transfusion)

ECU = eculizumab; ITT = intention to treat; LDH = lactate dehydrogenase; PEG = pegcetacoplan; SD = standard deviation.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Figure 8: LDH Level Over Time in the PEGASUS Trial — Whole Study Analysis (ITT)

ALP-2 = pegcetacoplan; ITT = intention to treat; LDH = lactate dehydrogenase; LLN = lower limit of normal; SE = standard error; ULN = upper limit of normal.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan. Study periods were as follows: run-in period (baseline to day –1); randomized controlled period (day 1 to week 16); open-label pegcetacoplan period (week 17 to week 48); and follow-up period (week 49 to week 60). The eculizumab arm refers to patients who received eculizumab in the randomized controlled period and subsequently completed a 4-week run-in period (week 17 to week 20) with concurrent treatment with eculizumab and pegcetacoplan, followed by pegcetacoplan monotherapy until week 48.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Extravascular Hemolysis

Absolute Reticulocyte Count

As summarized in Table 34, the mean change in ARC level from week 17 to week 48 (secondary end point) was –6.5 × 10⁹ cells/L (SD = 26.5 × 10⁹ cells/L) in the pegcetacoplan to pegcetacoplan group and –121.2 × 10⁹ cells/L (SD = 70.8 × 10⁹ cells/L) in the eculizumab to pegcetacoplan group. The mean change from baseline in ARC at week 48 (secondary end point) was –135.6 × 10⁹ cells/L (SD = 67.9 × 10⁹ cells/L) in the pegcetacoplan to pegcetacoplan group and –128.2 × 10⁹ cells/L (SD = 59.6 × 10⁹ cells/L) in the eculizumab to pegcetacoplan group. The change in ARC level over time (whole study) is shown in Figure 9.

Table 34: Change From Baseline in ARC in the PEGASUS Trial — Open-Label Pegcetacoplan Period and Whole Study Analyses (ITT; Uncensored for Transfusion)

ARC = absolute reticulocyte count; ECU = eculizumab; ITT = intention to treat; PEG = pegcetacoplan; SD = standard deviation.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Health Care Resource Utilization

This end point was not measured in the study.

Harms

Only those harms identified in the open-label pegcetacoplan period are reported below. Refer to Table 35 for detailed harms data.

Adverse Events

TEAEs were reported in 92.2% of patients, with the most common TEAEs (≥ 10%) being hemolysis, nasopharyngitis, diarrhea, cough, injection site erythema, fatigue, headache, and upper respiratory tract infection.

Serious Adverse Events

Serious TEAEs were reported in 23.4% of patients, with the most common TEAEs being hemolysis, reported in 5 (6.5%) patients, and gastroenteritis, reported in 2 (2.6%) patients.

Figure 9: ARC Over Time in the PEGASUS Trial — Whole Study Analysis (ITT)

ALP-2 = pegcetacoplan; ARC = absolute reticulocyte count; ITT = intention to treat; LLN = lower limit of normal; SE = standard error; ULN = upper limit of normal.

Note: Baseline was defined as the average of measurements recorded before the first dose of pegcetacoplan. Study periods were as follows: run-in period (baseline to day –1); randomized controlled period (day 1 to week 16); open-label pegcetacoplan period (week 17 to week 48); and follow-up period (week 49 to week 60). The eculizumab arm refers to patients who received eculizumab in the randomized controlled period and subsequently completed a 4-week run-in period (week 17 to week 20) with concurrent treatment with eculizumab and pegcetacoplan, followed by pegcetacoplan monotherapy until week 48.

Source: PEGASUS Clinical Study Report (48 weeks).³⁶

Withdrawals Due to Adverse Events

Nine (11.7%) patients discontinued treatment due to a TEAE of hemolysis (2 patients) and bone marrow failure, hemolytic anemia, acute myeloid leukemia, diffuse large B-cell lymphoma, intestinal ischemia, COVID-19, and hypersensitivity pneumonitis (1 patient each).

Mortality

One death (1.3%) due to COVID-19 infection was reported.

Notable Harms

There were no serious infections known to be caused by an encapsulated organism. Injection site–related TEAE was reported in 20 (26.0%) patients. Injection site erythema (11.7%), induration (6.5%),and pruritis (6.5%) were the most common injection site–related TEAEs. No patient had a positive antipegcetacoplan antibody response. Two (2.6%) patients reported a thrombotic event, neither of which was deemed by the sponsor to be related to pegcetacoplan. One event occurred in the setting of diffuse large B-cell lymphoma, sepsis, and breakthrough hemolysis, and the other occurred in the setting of pneumonia infection and renal failure. There was no report of renal failure and pulmonary hypertension. Hemolysis was reported in 15 (19.5%) patients.

Table 35: Summary of Harms in the PEGASUS Trial — Open-Label Pegcetacoplan Period (Safety Set)

ECU = eculizumab; NR = not reported; PEG = pegcetacoplan; TEAE = Treatment-emergent adverse event.

Note: A TEAE was defined as an AE that commenced on or after the first study drug administration or an AE that increased in severity after pretreatment.

^aFrequency > 10%.

^bOccurred in ≥ 2 patients.

Critical Appraisal

Internal Validity

The single-arm extension period of the PEGASUS trial provided evidence of the efficacy and safety of pegcetacoplan in patients with PNH who had inadequate response to eculizumab administered for up to 48 weeks. The noncomparative study design is a key limitation of the analysis. The lack of comparators precludes conclusions about the comparative efficacy of pegcetacoplan and eculizumab beyond the 16-week randomized controlled period. There is no control for confounding factors in a nonrandomized study, so it is difficult to determine whether the observed effects can be attributed to pegcetacoplan alone. There was no formal statistical testing, and results were presented using descriptive statistics. The open-label design can also introduce uncertainties about subjective outcomes (FACIT-Fatigue, LASA, EORTC QLQ-C30, harms), as reporting of outcomes could be influenced by knowledge of treatment assignment.

External Validity

Much of the appraisal of the RCT with respect to population generalizability also applies to the extension period. In addition, although the study results seem to suggest that the efficacy and safety of pegcetacoplan can be maintained over the long-term, outcomes such as breakthrough hemolysis, survival, thrombosis, and other complications of PNH require a much longer duration of follow-up before firm conclusions can be drawn, given that PNH is a chronic condition.

Discussion

Summary of Available Evidence

This report summarizes the evidence for pegcetacoplan in the treatment of PNH based on 1 phase III RCT with a single-arm extension period and 1 ITC.

One study, PEGASUS, met the inclusion criteria for the Systematic Review section. PEGASUS was a phase III, open-label, RCT that aimed to demonstrate the superiority of pegcetacoplan to eculizumab in adult patients with PNH who continued to have Hb levels less than 10.5 g/dL, despite treatment with eculizumab (N = 80) at a stable dose for at least 3 months. In the 16-week randomized controlled period, the change from baseline at week 16 in Hb (primary end point), transfusion avoidance, and change in baseline at week 16 in ARC, LDH, and FACIT-Fatigue score (key secondary end points) were assessed. All patients had adequate bone marrow function and no history of bone marrow transplant or hereditary complement deficiency. At baseline, the mean age was 48.8 years (SD = 16.0 years), and the majority of patients were female and white. Patients had received eculizumab for a mean duration of approximately 5 years before the study, and 30% of them received eculizumab at a dose higher than the maintenance dose approved for PNH by Health Canada. The study population had a mean Hb level of 8.7 g/dL (SD = 1.0 g/dL), reasonable control of IVH (mean LDH less than 1.5 × ULN), elevated mean ARC and bilirubin levels, and low haptoglobin levels, consistent with the signs of EVH.

Safety and efficacy results from the 32-week single-arm extension period for the PEGASUS trial (N = 77), during which all patients received pegcetacoplan, were also submitted by the sponsor and are presented in this report.

One sponsor-submitted ITC was presented in this report. Given the lack of direct comparative evidence between pegcetacoplan and ravulizumab, the sponsor performed an anchored MAIC to evaluate the relative efficacy of pegcetacoplan to ravulizumab in adult patients with PNH previously treated with eculizumab. The analysis was informed by patient-level data from the PEGASUS study, comparing pegcetacoplan and eculizumab, and aggregate patient data from the ALXN study, comparing ravulizumab and eculizumab. Outcomes analyzed were transfusion avoidance, number of packed RBCs transfused, Hb level stabilization, change from baseline in LDH level, LDH level normalization, fatigue and fatigue symptoms, global health status, and physical functioning. After matching, 68 patients from the PEGASUS study and 195 patients from the ALXN study were included.

Interpretation of Results

Efficacy

Evidence from the pivotal, phase III PEGASUS trial supported the superiority of pegcetacoplan to eculizumab with respect to the primary end point of change from baseline in Hb level at week 16 in adult patients with PNH who had an inadequate response to eculizumab, addressing a key treatment outcome noted by both patients and clinicians. The clinical experts consulted by CADTH considered the benefits of pegcetacoplan on Hb to be clinically meaningful. It has been proposed that Hb level is a strong surrogate biomarker for clinical benefits in patients with sickle cell disease receiving stem cell or gene therapy,^24,25 but evidence for PNH is scarce due to rarity of the disease. The sponsor noted that thromboembolic events have been linked to hemolysis in this patient population, potentially through the buildup of cell-free plasma Hb.^14,37-41 Nonetheless, it is challenging to draw conclusions about long-term outcomes (e.g., thrombosis, pulmonary hypertension, chronic kidney disease) based on Hb findings because data relating the 2 are limited.

Transfusion dependence poses a significant treatment burden to patients and is associated with AEs and poor QoL, per clinician input. Transfusion avoidance was much more frequently observed in the pegcetacoplan arm than in the eculizumab arm; however, only noninferiority between treatments was concluded because superiority was not tested, in accordance with the hierarchal testing procedure. The clinical experts considered the results to be supportive of the benefit of pegcetacoplan in improving anemia, given that transfusion needs are dependent on Hb level.

Fatigue, the most commonly reported anemia-related symptom of PNH, was assessed using the key secondary end point of change from baseline at week 16 in FACIT-Fatigue score. The analysis showed that patients receiving pegcetacoplan had more improvement in mean fatigue scores from baseline at week 16 than patients receiving eculizumab; however, no conclusions on noninferiority or superiority could be drawn because such statistical tests were not conducted, per the hierarchal testing procedure. Results were in favour of pegcetacoplan with respect to the LASA scale and the EORTC QLQ-C30 global health status/QoL and fatigue subscales, but not with respect to other symptom scales relevant to PNH, such as pain and dyspnea. However, it should be noted that these HRQoL outcomes are subject to a risk of type I error due to the lack of adjustment for multiplicity and a risk of reporting bias due to the open-label design and a large amount of missing data due to censoring for transfusion. Because these patient-reported outcome instruments are not used routinely in clinical practice and have not been validated in patients with PNH, it is impossible to draw any definitive conclusions regarding the effect of pegcetacoplan on fatigue and HRQoL. Nonetheless, based on their clinical experience, the clinical experts expected that the mean change in Hb observed in the pegcetacoplan arm would result in noticeable improvements in fatigue, activities of daily living, and HRQoL in patients.

Hemolytic markers, used by clinicians to assess disease activity, were measured in the study as supportive evidence for the control of intravascular and extravascular hemolysis. The study could not demonstrate noninferiority between the interventions with respect to the key secondary end point of change from baseline at week 16 in LDH level, a biomarker of IVH. A goal of treatment for PNH is to achieve sustained LDH control, per clinician input. Given that IVH was reasonably controlled at baseline, as expected with prior eculizumab treatment, and remained so at week 16 in both groups, the clinical experts were not concerned about the inability to conclude noninferiority regarding change in LDH. Noninferiority with respect to the key secondary end point of change from baseline at week 16 in ARC, an indicator of EVH, was established between the interventions. Despite a more notable reduction in ARC from baseline in the pegcetacoplan arm than in the eculizumab arm, no conclusion of superiority could be drawn because such test was not conducted, per the hierarchal testing procedure. Results of the indirect bilirubin analysis were also in favour of pegcetacoplan. Although results of the haptoglobin analysis did not favour pegcetacoplan, the clinical experts expressed no concerns because haptoglobin is a poor measure of treatment response. In addition, results of the indirect bilirubin and haptoglobin analyses should be interpreted with caution because of the increased risk of type I error due to the lack of control for multiplicity. In consultation with the clinical experts, the CADTH review team considered that the overall evidence related to hemolytic markers supports pegcetacoplan as an effective treatment for controlling both intravascular and extravascular hemolysis.

Responder analyses were conducted for the primary and key secondary outcomes, including Hb response, Hb normalization, LDH normalization, and ARC normalization in the absence of transfusion, as well as for FACIT-Fatigue score. Results were in favour of pegcetacoplan across all analyses, with numerically higher proportions of patients achieving response or normalization with pegcetacoplan than with eculizumab. However, the difference between treatment arms has not been tested for statistical significance and should be interpreted with caution. Further, the FACIT-Fatigue responder analysis was subject to some uncertainties because an MID estimate has not been established in the study population of patients with C5 inhibitor experience.

No definitive conclusion can be drawn with respect to long-term outcomes such as survival, breakthrough hemolysis, thrombosis, and other complications of PNH, or with respect to health care utilization because these outcomes were not evaluated in the efficacy analysis. Although they were included in the harms analysis (except health care utilization), results should be considered exploratory in the absence of formal hypothesis testing. The use of an Hb level of less than 10.5 g/dL as the cut-off for study eligibility, the exclusion of patients with certain cardiovascular diseases or receiving QT-prolonging medications, and the absence of evidence in patients with intolerance to eculizumab introduced some uncertainties to the generalizability of the study findings, although unlikely to be significant.

Results of the open-label extension period of the PEGASUS trial suggested that the benefits of pegcetacoplan with respect to Hb, transfusion avoidance, fatigue, HRQoL, and hemolytic parameters (LDH and ARC) were sustained through week 48. However, the noncomparative design of the extension period meant that the comparative efficacy of pegcetacoplan and eculizumab beyond the 16-week randomized controlled period could not be established, which is a limitation given the chronic nature of the disease.

In the sponsor-submitted anchored MAIC, after matching and anchoring on eculizumab, treatment with pegcetacoplan, compared with ravulizumab, was associated with more transfusion avoidance, more Hb level stabilization, more LDH level normalization in the absence of transfusions, and fewer units of packed RBCs transfused. In addition, treatment with pegcetacoplan, compared with ravulizumab, was associated with improvements in fatigue, global health status, physical functioning, and fatigue symptoms. There was no difference in mean change from baseline in LDH levels.

The anchored MAIC had several strengths and limitations. Strengths included anchored comparisons, which used a common comparator, eculizumab; relevant effect modifiers, which were matched in the weighting process separately for clinical and hematological outcomes and fatigue and QoL outcomes; and consistency in results, which were noted in sensitivity analyses that used anchored comparisons based on the unweighted sample before matching and unanchored comparisons that included both effect modifiers and prognostic variables. Limitations included the lack of matching of 2 clinically important effect modifiers (Hb level and history of transfusions) and the heterogeneity between studies regarding duration of follow-up (i.e.,16 weeks for the PEGASUS study versus 26 weeks for the ALXN study), treatment administration schedule, and dosing regimen. Given the strengths and limitations of the anchored MAIC, there is uncertainty in the relative treatment effect estimates that favour pegcetacoplan over ravulizumab.

Harms

In the randomized controlled period of the PEGASUS trial, the most common TEAEs associated with pegcetacoplan (reported in at least 20% of patients) were injection site–related reactions and diarrhea, both of which were more commonly reported in the pegcetacoplan arm than the eculizumab arm, but none were serious or led to treatment discontinuation. Compared with eculizumab, pegcetacoplan was associated with a notably lower incidence of headache and breakthrough hemolysis. Breakthrough hemolysis resulted in dose escalation and discontinuation of pegcetacoplan in 2 (4.9%) and 3 (7.3%) patients, respectively. The occurrence of AEs and serious AEs during the extension period was similar to that during the randomized controlled period. The study, overall, had no reports of serious infection caused by encapsulated bacteria. Two patients in the pegcetacoplan arm experienced thrombosis during the open-label period, but neither case was deemed by the sponsor to be related to pegcetacoplan.

The clinical experts noted that most AEs associated with pegcetacoplan were observed in clinical practice were mild, with the exception of hemolysis, which has the potential to become serious. Nonetheless, the experts considered the lower incidence of breakthrough hemolysis with pegcetacoplan compared with eculizumab to be favourable. To gain certainty in the incidence of breakthrough hemolysis and dose escalation, a longer duration of follow-up, of at least 2 years, and a larger sample size would be required to adequately account for breakthrough hemolysis due to situational events (e.g., infection, surgery, pregnancy, vaccination), according to the clinical experts. The same also applies to long-term outcomes such as thrombosis and survival. A long-term extension study of patients who previously completed a pegcetacoplan study that aims to provide safety data for up to 2 years is ongoing and results will be forthcoming.³⁵

Conclusions

In the PEGASUS trial, pegcetacoplan demonstrated a clinically meaningful improvement in Hb level compared with eculizumab in a 16-week randomized controlled period in a study population that was representative of patients with PNH who had clinically significant anemia, despite an adequate trial of eculizumab, and had signs of EVH. The evidence strongly suggested that Hb improvement translated into an improvement in transfusion avoidance with pegcetacoplan over eculizumab. Results also suggested that pegcetacoplan could reduce fatigue compared with eculizumab, but the magnitude of benefit and its clinical relevance is uncertain. Analyses of hemolytic markers lent support to the ability of pegcetacoplan to reduce EVH and maintain IVH control. The benefits of pegcetacoplan were sustained through week 48 in the extension period, but the single-arm design precludes conclusions on the comparative efficacy between pegcetacoplan and eculizumab beyond week 16. The sponsor-submitted MAIC assessing the comparative efficacy of pegcetacoplan with ravulizumab showed transfusion avoidance, number of packed RBCs transfused, Hb level stabilization, LDH level normalization, fatigue and fatigue symptoms, global health status, and physical functioning in favour of pegcetacoplan; however, the findings should be interpreted with caution, given the lack of matching of some effect modifiers and the heterogeneity in study designs and populations. The safety profile of pegcetacoplan was generally similar to that of eculizumab, although there was a higher incidence of nonserious injection site–related reactions and diarrhea. A longer duration of follow-up is required to provide certainty on the incidence of breakthrough hemolysis, thrombosis, and survival with pegcetacoplan treatment.

References

1.Patriquin CJ, Kiss T, Caplan S, et al. How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol. 2019;102(1):36-52. PubMed

2.Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811. PubMed

3.Hill A, Platts P, Smith A, Richards SJ, Cullen M. The incidence and prevalence of paroxysmal nocturnal hemoglobinuria (PNH) and survival of patients in Yorkshire [abstract]. Presented at: 64th ASH Annual Meeting; New Orleans, LA; Dec 10-13, 2022. Blood. 2006;108(11):985. https://www.sciencedirect.com/science/article/pii/S0006497118424251. Accessed 2022 Nov 8.

4.PrEmpaveliTM (pegcetacoplan): solution for infusion: 54 mg/mL solution for infusion for subcutaneous use [draft product monograph]. Stockholm (SE): Swedish Orphan Biovitrum AB; 2022.

5.Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028-1037. PubMed

6.Clinical Study Report: APL2-302. A phase 3, randomized, multicenter, open-label, active-comparator controlled study to evaluate the efficacy and safety of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH) week 16 analysis [internal sponsor's report]. Waltham (MA): Apellis Pharmaceuticals; 2020.

7.Bhak RH, Mody-Patel N, Baver SB, et al. Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison. Curr Med Res Opin. 2021;37(11):1913-1923. PubMed

8.Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540-549. PubMed

9.Brodsky RA. Clinical manifestations and diagnosis of paroxysmalnocturnal hemoglobinuria. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2022: https://www.uptodate.com. Accessed 2022 Sep 14.

10.Nishimura JI, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). 2004;83(3):193-207. PubMed

11.Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996;348(9027):573-577. PubMed

12.Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117(25):6786-6792. PubMed

13.DeZern AE, Dorr D, Brodsky RA. Predictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Eur J Haematol. 2013;90(1):16-24. PubMed

14.Risitano AM, Marotta S, Ricci P, et al. Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Front Immunol. 2019;10:1157. PubMed

15.Brodsky RA. Treatment and prognosis of paroxysmal nocturnalhemoglobinuria. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2022: https://www.uptodate.com. Accessed 2022 Nov 08.

16.Cancado RD, Araujo ADS, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348. PubMed

17.Hillmen P, Muus P, Roth A, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162(1):62-73. PubMed

18.PrSoliris® (eculizumab): 30 mL parenteral solution (10 mg/mL) [product monograph]. Zurich (CH): Alexion Pharma GmbH; 2021 Mar 25: https://pdf.hres.ca/dpd_pm/00060546.PDF. Accessed 2022 Nov 08.

19.PrUltomiris™ (ravulizumab): 10 mg/mL concentrate for solution for infusion [product monograph]. Zurich (CH): Alexion Pharma GmbH; 2021 Sep 22: https://pdf.hres.ca/dpd_pm/00063038.PDF. Accessed 2022 Nov 08.

20.McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40-46. PubMed

21.Grey matters: a practical tool for searching health-related grey literature. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/grey-matters. Accessed 2022 Sep 20.

22.Center for Drug Evaluation Research. Integrated review: Empaveli (pegcetacoplan) for subcutaneous infusion. Company: Apellis Pharamceuticals, Inc. Application No.:NDA 215014. Approval date: 05/14/2021 (FDA approval package). Pegcetacoplan (Empaveli) Subcutaneous infusion. . Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2021: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215014Orig1s000IntegratedR.pdf. Accessed 2022 Oct 12.

23.Cella D, Sarda SP, Hsieh R, et al. Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study. Ann Hematol. 2022;101(9):1905-1914. PubMed

24.Farrell AT, Panepinto J, Desai AA, et al. End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings. Blood Adv. 2019;3(23):4002-4020. PubMed

25.Lehrer-Graiwer J, Yokoshima L, Tong B, Love TW. Accelerated approval of Oxbryta® (voxelotor): a case study on novel endpoint selection in sickle cell disease. Contemp Clin Trials. 2020;98:106161. PubMed

26.Weitz I, Meyers G, Lamy T, et al. Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria. Intern Med J. 2013;43(3):298-307. PubMed

27.Cella D, Johansson P, Ueda Y, et al. Clinically important difference for the FACIT-fatigue scale in paroxysmal nocturnal hemoglobinuria: a derivation from international PNH registry patient data [poster]. Presented at: BSH 2022 ASM; Manchester, UK; Apr 3-5, 2022. 2022: https://www.postersessiononline.eu/173580348_eu/congresos/BSH2022/aula/-PO_96_BSH2022.pdf. Accessed 2022 Oct 16.

28.Locke DE, Decker PA, Sloan JA, et al. Validation of single-item linear analog scale assessment of quality of life in neuro-oncology patients. J Pain Symptom Manage. 2007;34(6):628-638. PubMed

29.Barcellini W, Fattizzo B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Dis Markers. 2015;2015:635670. PubMed

30.Jang JH, Kim JS, Yoon SS, et al. Predictive factors of mortality in population of patients with paroxysmal nocturnal hemoglobinuria (PNH): results from a Korean PNH registry. J Korean Med Sci. 2016;31(2):214-221. PubMed

31.Lee JW, Jang JH, Kim JS, et al. Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. Int J Hematol. 2013;97(6):749-757. PubMed

32.Shih AW, McFarlane A, Verhovsek M. Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol. 2014;89(4):443-447. PubMed

33.Statistical Analysis Plan: Study 302. A phase 3, randomized, multicenter, open-label, active-comparator controlled study to evaluate the efficacy and safety of ALP-2 in patients with paroxysmal nocturnal hemoglobinuria (PNH) week 16 analysis [internal sponsor's report]. Waltham (MA): Apellis Pharmaceuticals; 2019.

34.de Latour RP, Szer J, Weitz IC, et al. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022;9(9):e648-e659. PubMed

35.Hoffman K, Machaidze Z, Yeh M, Weitz IC. Evaluation of the long-term safety and efficacy of pegcetacoplan treatment for paroxysmal nocturnal hemoglobinuria patients: an extension study [abstract]. Presented at: 63rd ASH Annual Meeting; Atlanta, GA; Dec 11-14, 2021. Blood. 2021;138(Suppl 1):2175. 10.1182/blood-2021-148042. Accessed 2022 Nov 8.

36.Clinical Study Report: APL2-302. A phase 3, randomized, multicenter, open-label, active-comparator controlled study to evaluate the efficacy and safety of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH) week 48 analysis [internal sponsor's report]. Waltham (MA): Apellis Pharmaceuticals; 2021.

37.Audebert HJ, Planck J, Eisenburg M, Schrezenmeier H, Haberl R. Cerebral ischemic infarction in paroxysmal nocturnal hemoglobinuria report of 2 cases and updated review of 7 previously published patients. J Neurol. 2005;252(11):1379-1386. PubMed

38.Gralnick HR, Vail M, McKeown LP, et al. Activated platelets in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1995;91(3):697-702. PubMed

39.Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003;102(10):3587-3591. PubMed

40.Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol. 2003;77(2):113-120. PubMed

41.Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662. PubMed

42.Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376. PubMed